Napht-2-ylacetic acid derivatives to treat aids

ABSTRACT

The invention provides compounds of formula (I): or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula (I), intermediates useful for preparing compounds of formula I and therapeutic methods for treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal using compounds of formula (I).

This patent application claims the benefit of priority of U.S.application Ser. No. 61/361,314, filed Jul. 2, 2010.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) infection and related diseases are amajor public health problem worldwide. Human immunodeficiency virus type1 (HIV-1) encodes three enzymes which are required for viralreplication: reverse transcriptase, protease, and integrase. Althoughdrugs targeting reverse transcriptase and protease are in wide use andhave shown effectiveness, particularly when employed in combination,toxicity and development of resistant strains have limited theirusefulness (Palella, et al N. Engl. J. Med. (1998) 338:853-860; Richman,D. D. Nature (2001) 410:995-1001). Accordingly, there is a need for newagents that inhibit the replication of HIV. There is also a need foragents that are directed against alternate sites in the viral life cycleincluding agents that target the interaction of Lens Epithelial DerivedGrowth Factor (LEDGF/p75) and HIV-1 integrase.

SUMMARY OF THE INVENTION

In one embodiment, the invention provides a compound of the inventionwhich is a compound of formula I:

wherein:

R¹ is R^(1a) or R^(1b);

R² is R^(2a) or R^(2b);

R³ is R^(3a) or R^(3b);

R^(3′) is R^(3a′) or R^(3b′);

R⁴ is R^(4a) or R^(4b);

R⁵ is R^(5a) or R^(5b);

R⁶ is R^(6a) or R^(6b);

R⁷ is R^(7a) or R^(7b);

R⁸ is R^(8a) or R^(8b);

R^(1a) is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)Ro¹, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl and wherein each R¹⁰ is independently selected fromR¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and—C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

wherein any aryl, heterocycle and heteroaryl of R^(1a) is optionallysubstituted with one or more (e.g. 1, 2 or 3) Z^(I) groups;

R^(1b) is selected from:

a)-(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³,—O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³,—SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴,—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl,—(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, —(C₃-C₇)halocarbocycle,—NR_(a)SO₂NR_(c)R_(d), NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₃-C₇)halocarbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycleand heteroaryl, either alone or as part of a group, is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle wherein the(C₃-C₇)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z² groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl,—X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and—X(C₁-C₆)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or5) Z³ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle, is substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl, heteroaryl and heterocycle, eitheralone or as part of a group, is substituted with one or more (e.g. 1, 2,3, 4 or 5) Z⁵ groups and optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein any (C₁-C₆)alkyl, as part of a group is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R^(2a) is selected from:

a) H, (C₁-C₆)alkyl and —O(C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl,heterocycle and heteroaryl are each optionally substituted with one ormore (e.g. 1, 2 or 3) Z¹¹ groups;

d) —OH, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl,—O(C₃-C₇)cycloalkyl, —Oaryl, —Oheterocycle and —Oheteroaryl; and

e) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰, and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═)OR¹¹ and —C(═O)N(R⁹)R¹⁰,wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl;

R^(2b) is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³,—O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³,—SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴,—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³, —(C₃-C₇)halocarbocycle,—NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₃-C₇)halocarbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycleand heteroaryl, either alone or as part of a group, is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle, wherein the(C₃-C₇)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z² groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

d) —X(C₁-C₆)alkyl, X(C₁-C₆)haloalkyl, X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and—X(C₁-C₆)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or5) Z³ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle is substituted with one or more (e.g. 1, 2, 3, 4or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl, heteroaryl and heterocycle, eitheralone or as part of a group, is substituted with one or more (e.g. 1, 2,3, 4 or 5) Z⁵ groups and optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein any (C₁-C₆)alkyl, as part of a group is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R^(3a) is (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl-aryl,—(C₁-C₆)alkyl-heterocycle, —(C₁-C₆)alkyl-heteroaryl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,—O(C₃-C₇)cycloalkyl, —Oaryl, —O(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl-aryl, —O(C₁-C₆)alkyl-heterocycle or—O(C₁-C₆)alkyl-heteroaryl, wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₂-C₆)alkenyl or (C₂-C₆)alkynyl of R^(3a) either alone or as part of agroup, is optionally substituted with one or more (e.g. 1, 2 or 3)groups selected from —O(C₁-C₆)alkyl, halo, oxo and —CN, and wherein any(C₃-C₇)cycloalkyl, aryl, heterocycle or heteroaryl of R^(3a) eitheralone or as part of a group, is optionally substituted with one or more(e.g. 1, 2 or 3) groups selected from (C₁-C₆)alkyl, —O(C₁-C₆)alkyl,halo, oxo and —CN; and R^(3a′) is H;

R^(3b) is —(C₇-C₁₄)alkyl, —(C₃-C₇)carbocycle, aryl, heteroaryl,heterocycle, —(C₁-C₆)alkylOH, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹²,—(C₁-C₆)alkyl-O—(C₂-C₆)alkenyl-Z¹², —(C₁-C₆)alkyl-O—(C₂-C₆)alkynyl-Z²,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z², —(C₁-C₆)alkyl-S—(C₂-C₆)alkenyl-Z¹²,—(C₁-C₆)alkyl-S—(C₂-C₆)alkynyl-Z¹², —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-Z¹²,—(C₁-C₆)alkyl-S(O)—(C₂-C₆)alkenyl-Z¹²,—(C₁-C₆)alkyl-S(O)—(C₂-C₆)alkynyl-Z¹²,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹²,—(C₁-C₆)alkyl-SO₂—(C₂-C₆)alkenyl-Z¹²,—(C₁-C₆)alkyl-SO₂—(C₂-C₆)alkynyl-Z¹², —(C₁-C₆)alkyl-NR_(a)R_(b),—(C₁-C₆)alkylOC(O)—NR_(c)R_(d), —(C₁-C₆)alkyl-NR_(a)—C(O)—OR_(b),—(C₁-C₆)alkyl-NR_(a)—C(O)—NR_(a)R_(b), —(C₁-C₆)alkyl-SO₂(C₁-C₆)alkyl,—(C₁-C₆)alkyl-SO₂NR_(c)R_(d), —(C₁-C₆)alkyl-NR_(a)SO₂NR_(c)R_(d),—(C₁-C₆)alkyl-NR_(a)SO₂O(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-NR_(a)SO₂Oaryl,—(C₁-C₆)alkyl-NR_(a)—SO₂—(C₁-C₆)alkyl,—(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₁-C₆)alkyl,—(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkenyl,—(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkynyl,—(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, —(C₁-C₆)alkyl-NR_(a)—SO₂-heteroaryl,—(C₁-C₆)alkyl-NR_(a)—SO₂-heterocycle, —O(C₇-C₁₄)alkyl,—O(C₁-C₆)alkyl-NR_(a)R_(b), —O(C₁-C₆)alkylOC(O)—NR_(c)R_(d),—O(C₁-C₆)alkyl-NR_(a)—C(O)—OR_(b),—O(C₁-C₆)alkyl-NR_(a)—C(O)—NR_(a)R_(b),—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkenyl,—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkynyl,—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, —O(C₁-C₆)alkyl-NR_(a)—SO₂-heteroaryl,—O(C₁-C₆)alkyl-NR_(a)—SO₂-heterocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂—NR_(a)R_(b),—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, —O(C₁-C₆)alkyl-NR_(a)SO₂NR_(c)R_(d),—O(C₁-C₆)alkyl-NR_(a)SO₂O(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)SO₂Oaryl, —Oheteroaryl, —Oheterocycle,—Sheteroaryl, —Sheterocycle, —S(O)heteroaryl, —S(O)heterocycle,—SO₂heteroaryl or —SO₂heterocycle, wherein any (C₁-C₆)alkyl,—(C₇-C₁₄)alkyl, aryl, (C₃-C₇)carbocycle, heteroaryl or heterocycle ofR^(3b), either alone or as part of a group, is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, and R^(3b′) is H,(C₁-C₆)alkyl or —O(C₁-C₆)alkyl; or R^(3b) and R^(3b′) together with thecarbon to which they are attached form a heterocycle or(C₃-C₇)carbocycle which heterocycle or (C₃-C₇)carbocycle of R^(3b) andR^(3b′) together with the carbon to which they are attached isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

R^(4a) is selected from aryl, heterocycle and heteroaryl, wherein anyaryl, heterocycle and heteroaryl of R^(4a) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) groups each independentlyselected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl isoptionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo;

R^(4b) is selected from;

a) (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein(C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) (C₃-C₁₄)carbocycle, wherein (C₃-C₁₄)carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle;

c) spiro-heterocycle and bridged-heterocycle, wherein spiro-heterocycleand bridged-heterocycle are optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups, or wherein two Z¹ groups together withthe atom or atoms to which they are attached optionally form a(C₃-C₇)carbocycle or heterocycle; and

d) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle andbridged-heterocycle, wherein aryl, heteroaryl, spiro-heterocycle,fused-heterocycle and bridged-heterocycle heterocycle are eachindependently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁷groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups; or

R⁴ and R³ together with the atoms to which they are attached form amacroheterocycle or a macrocarbocycle wherein any macroheterocycle ormacrocarbocycle of R⁴ and R³ together with the atoms to which they areattached may be optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups; and R^(3′) is H, (C₁-C₆)alkyl or —O(C₁-C₆)alkyl;

R^(5a) is selected from:

a) halo, nitro and cyano;

b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl,heterocycle and heteroaryl are each optionally substituted with one ormore (e.g. 1, 2 or 3) Z¹¹ groups; and

c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰, and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰,wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl;

R^(5b) is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkylS(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkylSO₂(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,—(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, (C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³ wherein any (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, eitheralone or as part of a group, is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,fused-bicyclic carbocycle or bridged-bicyclic carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle wherein the(C₃-C₇)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z² groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl,—X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and—X(C₁-C₆)haloalkyl, is substituted with one or more Z³ groups andoptionally substituted with one or more Z¹ groups, and wherein any—X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle issubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups andoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl, heteroaryl and heterocycle, eitheralone or as part of a group, is substituted with one or more (e.g. 1, 2,3, 4 or 5) Z⁵ groups and optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl, where (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein any (C₁-C₆)alkyl, as part of a group, is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R^(6a) is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰,wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl;

and wherein any aryl, heterocycle and heteroaryl of R^(6a) is optionallysubstituted with one or more (e.g. 1, 2 or 3) Z¹ groups;

R^(6b) is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OR_(a), —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a),—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or aspart of a group, is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)cycloalkyl or heterocycle, wherein the(C₃-C₇)cycloalkyl or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z² groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl,—X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and—X(C₁-C₆)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or5) Z³ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle, are each independently substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z⁴ groups and optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl, heteroaryl and heterocycle, eitheralone or as part of a group, is substituted with one or more (e.g. 1, 2,3, 4 or 5) Z⁵ groups and optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein any (C₁-C₆)alkyl, as part of a group, is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R^(7a) is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹¹,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰,

wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl; and

wherein any aryl, heterocycle and heteroaryl of R^(7a) is optionallysubstituted with one or more (e.g. 1, 2 or 3) Z¹⁰ groups;

R^(7b) is selected from:

a) —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³,—O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³,—SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴,—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z³,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,—(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₃-C₇)halocarbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycleand heteroaryl, either alone or as part of a group, is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle wherein the(C₃-C₇)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z² groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

d) —X(C₁-C₆)alkyl, X(C₁-C₆)haloalkyl, X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and—X(C₁-C₆)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or5) Z³ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle is substituted with one or more (e.g. 1, 2, 3, 4or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl, heteroaryl and heterocycle, eitheralone or as part of a group, is substituted with one or more (e.g. 1, 2,3, 4 or 5) Z⁵ groups and optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or moreZ⁶ groups and optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein any (C₁-C₆)alkyl, as part of a group, is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R^(8a) is selected from:

a) halo, nitro and cyano;

b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl,heterocycle and heteroaryl are each optionally substituted with one ormore (e.g. 1, 2 or 3) Z¹¹ groups;

c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰,wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl;

R^(8b) is selected from:

a) —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³,—O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³,—SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴,—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or aspart of a group, is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z¹ groups:

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle,fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle wherein the(C₃-C₇)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z² groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl,—X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and—X(C₁-C₆)haloalkyl, is substituted with one or more (e.g. 1, 2, 3, 4 or5) Z³ groups and optionally substituted with one or more (e.g. 1, 2, 3,4 or 5) Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle is substituted with one or more (e.g. 1, 2, 3, 4or 5) Z⁴ groups and optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl, heteroaryl and heterocycle, eitheralone or as part of a group, is substituted with one or more (e.g. 1, 2,3, 4 or 5) Z⁵ groups and optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein any (C₁-C₆)alkyl, as part of a group, is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

or any of R^(5a) and R^(6a), R^(6a) and R^(7a), R^(7a) and R^(8a), R¹and R⁸ or R¹ and R² together with the atoms to which they are attachedform a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-memberedheterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2 or 3) substituents each independently selected from halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH,—O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and—N((C₁-C₆)alkyl)₂;

or any of R⁵ and R⁶, R⁶ and R⁷ or R⁷ and R⁸, together with the atoms towhich they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a4, 5, 6 or 7-membered heterocycle are each independently substitutedwith one or more (e.g. 1, 2 or 3) Z⁷ or Z⁸ groups, wherein when two Z⁷groups are on same atom the two Z⁷ groups together with the atom towhich they are attached optionally form a (C₃-C₇)carbocycle or 4, 5 or6-membered heterocycle;

or R¹ and R⁸ or R¹ and R² together with the atoms to which they areattached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-memberedheterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or7-membered heterocycle are each independently substituted with one ormore (e.g. 1, 2 or 3) Z⁷ or Z⁸ groups; wherein when two Z⁷ groups are onsame atom the two Z⁷ groups together with the atom to which they areattached optionally form a (C₃-C₇)carbocycle or 4, 5 or 6-memberedheterocycle;

X is independently selected from O, —C(O)—, —C(O)O—, —S—, —S(O)—, —SO₂.,—(C₁-C₆)alkylO—, —(C₁-C₆)alkylC(O)—, —(C₁-C₆)alkylC(O)O—,—(C₁-C₆)alkylS—, —(C₁-C₆)alkylS(O)— and —(C₁-C₆)alkylSO₂—;

each Z¹ is independently selected from halo, —NO₂, —OH, ═NOR_(a), —SH,—CN, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl, heterocycle,—O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl,—O(C₃-C₇)carbocycle, —O(C₃-C₇)halocarbocycle, —Oaryl, —Oheteroaryl,—Oheterocycle, —S(C₁-C₆)alkyl, —S(C₂-C₆)alkenyl, —S(C₂-C₆)alkynyl,—S(C₁-C₆)haloalkyl, —S(C₃-C₇)carbocycle, —S(C₃-C₇)halocarbocycle,—Saryl, —Sheteroaryl, —Sheterocycle, —S(O)(C₁-C₆)alkyl,—S(O)(C₂-C₆)alkenyl, —S(O)(C₂-C₆)alkynyl, —S(O)(C₁-C₆)haloalkyl,—S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle, —SO₂(C₁-C₆)alkyl,—S(O)aryl, —S(O)carbocycle, —S(O)heteroaryl, —S(O)heterocycle,—SO₂(C₂-C₆)alkenyl, —SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl,—SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, —SO₂aryl,—SO₂heteroaryl, —SO₂heterocycle, —SO₂NR_(c)R_(d), —NR_(c)R_(d),—NR_(a)C(O)R_(a), —NR_(a)C(O)OR_(a),—NR_(a)C(O)NR_(c)R_(d)—NR_(a)SO₂R^(b), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a), —C(O)R_(a),—C(O)OR_(b), —C(O)NR_(c)R_(d), and —OC(O)NR_(c)R_(d), wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl orheterocycle of Z¹, either alone or as part of a group, is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, —OH,—OR_(b), —CN, —NR_(a)C(O)₂R_(b), -heteroaryl, -heterocycle,—Oheteroaryl, —Oheterocycle, —NHheteroaryl, —NHheterocycle, or—S(O)₂NRCR_(d);

each Z² is independently selected from —NO₂, —CN, spiro-heterocycle,bridge-heterocycle, spiro-bicyclic carbocycle, bridged-bicycliccarbocycle, NR_(a)SO₂(C₃-C₇)carbocycle, —NR_(a)SO₂aryl,—NR_(a)SO₂heteroaryl, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z³ is independently selected from —NO₂, —CN, —OH, oxo, ═NOR_(a),thioxo, aryl, heterocycle, heteroaryl, (C₃-C₇)halocarbocycle,—O(C₁-C₆)alkyl, —O(C₃-C₇)carbocycle, —Ohalo(C₃-C₇)carbocycle, —Oaryl,—Oheterocycle, —Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle,—S(C₃-C₇)halocarbocycle, —Saryl, —Sheterocycle, —Sheteroaryl,—S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle,—S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SO₂aryl,—SO₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(b), —NR_(a)C(O)R_(b),—C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z⁴ is independently selected from halogen, (C₁-C₆)alkyl,(C₃-C₇)carbocycle, halo(C₁-C₆)alkyl, —NO₂, —CN, —OH, oxo, ═NOR_(a),thioxo, aryl, heterocycle, heteroaryl, (C₃-C₇)halocarbocycle,—O(C₁-C₆)alkyl, —O(C₃-C₇)carbocycle, —O(C₃-C₇)halocarbocycle, —Oaryl,—Oheterocycle, —Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle,—S(C₃-C₇)halocarbocycle, —Saryl, —Sheterocycle, —Sheteroaryl,—S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle,—S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SO₂aryl,—SO₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(b), —NR_(a)C(O)R_(a),—C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z⁵ is independently selected from —NO₂, —CN, —NR_(a)SO₂NR_(c)R_(d),—-NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —NR_(a)SO₂(C₁-C₆)alkyl,—NR_(a)SO₂(C₂-C₆)alkenyl, —NR_(a)SO₂(C₂-C₆)alkynyl,—NR_(a)SO₂(C₃-C₇)carbocycle, —NR_(a)SO₂(C₃-C₇)halocarbocycle,—NR_(a)SO₂aryl, —NR_(a)SO₂heteroaryl, —NR_(a)SO₂heteroaryl,—NR_(a)SO₂heterocycle, —NR_(a)C(O)alkyl, —NR_(a)C(O)alkenyl,—NR_(a)C(O)alkynyl, —NR_(a)C(O) (C₃-C₇)carbocycle,—NR_(a)C(O)(C₃-C₇)halocarbocycle, —NR_(a)C(O)aryl,—NR_(a)C(O)heteroaryl, —NR_(a)C(O)heterocycle, NR_(a)C(O)NR_(c)R_(d) andNR_(a)C(O)OR_(b);

each Z⁶ is independently selected from —NO₂, —CN, —NR_(a)R_(a),—NR_(a)C(O)R_(b), —NR_(a)C(O)OR_(b), —C(O)NR_(c)R_(d),(C₃-C₇)halocarbocycle, aryl, heteroaryl, heterocycle, —Oaryl,—Oheteroaryl, —Oheterocycle, —O(C₃-C₇)halocarbocycle, —O(C₁-C₆)alkyl,—O(C₃-C₇)carbocycle, —Ohalo(C₁-C₆)alkyl, —Saryl, —Sheteroaryl,—Sheterocycle, —S(C₃-C₇)halocarbocycle, —S(C₁-C₆)alkyl,—S(C₃-C₇)carbocycle, —S(C₁-C₆)haloalkyl, —S(O)aryl, —S(O)heteroaryl,—S(O)heterocycle, —S(O)(C₃-C₇)halocarbocycle, —S(O)(C₁-C₆)alkyl,—S(O)(C₃-C₇)carbocycle, —S(O)halo(C₁-C₆)alkyl, —SO₂aryl, —SO₂heteroaryl,—SO₂heterocycle, —SO₂(C₁-C₆)alkyl, —SO₂halo(C₁-C₆)alkyl,—SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, —SO₂NR_(c)R_(d),—NR_(a)SO₂(C₃-C₇)halocarbocycle, —NR_(a)SO₂aryl, —NR_(a)SO₂heteroaryl,—NR_(a)SO₂heteroaryl, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z⁷ is independently selected from —NO₂, ═NOR_(a), —CN,—(C₁-C₆)alkyl-Z¹², —(C₂-C₆)alkenyl-Z¹², —(C₂-C₆)alkenylOH,—(C₂-C₆)alkynyl-Z¹², —(C₂-C₆)alkynyl-OH, —(C₁-C₆)haloalkyl-Z¹²,—(C₁-C₆)haloalkylOH, —(C₃-C₇)carbocycle-Z¹², —(C₃-C₇)carbocycleOH,(C₃-C₇)halocarbocycle, —(C₁-C₆)alkylNR_(c)R_(d),—(C₁-C₆)alkylNR_(a)C(O)R_(a), —(C₁-C₆)alkylNR_(a)SO₂R_(a), aryl,heteroaryl, heterocycle, —O(C₁-C₆)alkyl-Z¹², —O(C₂-C₆)alkenyl,—O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl, —O(C₃-C₇)carbocycle,—O(C₃-C₇)halocarbocycle, —Oaryl, —O(C₁-C₆)alkylNR_(c)R_(d),—O(C₁-C₆)alkylNR_(a)C(O)R_(a), —O(C₁-C₆)alkylNR_(a)SO₂R_(a),—Oheteroaryl, —Oheterocycle, —S(C₁-C₆)alkyl-Z¹², —S(C₂-C₆)alkenyl,—S(C₂-C₆)alkynyl, —S(C₁-C₆)haloalkyl, —S(C₃-C₇)carbocycle,—S(C₃-C₇)halocarbocycle, —S(C₁-C₆)alkylNR_(c)R_(d),—S(C₁-C₆)alkylNR_(a)C(O)R_(a), —S(C₁-C₆)alkylNR_(a)SO₂R_(a), —Saryl,—Sheteroaryl, —Sheterocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₂-C₆)alkenyl,—S(O)(C₂-C₆)alkynyl, —S(O)(C₁-C₆)haloalkyl, —S(O)(C₃-C₇)carbocycle,—S(O)(C₃-C₇)halocarbocycle, —SO₂(C₁-C₆)alkyl,—S(O)(C₁-C₆)alkylNR_(c)R_(d), —S(O)(C₁-C₆)alkylNR_(a)C(O)R_(a),—S(O)(C₁-C₆)alkylNR_(a)SO₂R_(a), —S(O)aryl, —S(O)heteroaryl,—S(O)heterocycle, —SO₂(C₁-C₆)alkyl, —SO₂(C₂-C₆)alkenyl,—SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(C₃-C₇)carbocycle,—SO₂(C₃-C₇)halocarbocycle, —SO₂aryl, —SO₂heteroaryl, —SO₂heterocycle,—SO₂(C₁-C₆)alkylNR_(c)R_(d), —SO₂(C₁-C₆)alkylNR_(a)C(O)R_(a),—SO₂(C₁-C₆)alkylNR_(a)SO₂R_(a), —SO₂NR_(c)R_(d), —NR_(a)C(O)OR_(b),—NR_(a)C(O)NR_(c)R_(d)—NR_(a)SO₂R_(b), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a),—C(O)NR_(c)R_(d), and —OC(O)NRER_(d), wherein any (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle,(C₃-C₇)halocarbocycle, aryl, heteroaryl and heterocycle of Z⁷, eitheralone or as part of a group, is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b),heteroaryl, heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl,—NHheterocycle or —S(O)₂NR_(c)R_(d);

each Z⁸ is independently selected from —NO₂ and —CN;

each Z⁹ is independently selected from —(C₁-C₆)alkyl and —O(C₁-C₆)alkyl;

each Z¹ is independently selected from:

-   -   i) halo, oxo, thioxo, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl,        (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-(C₁-C₆)alkyl-, —OH,        —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —SH, —S(C₁-C₆)alkyl,        —SO(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and        —N((C₁-C₆)alkyl)₂;    -   ii) (C₁-C₆)alkyl optionally substituted with —OH,        —O—(C₁-C₆)haloalkyl or —O—(C₁-C₆)alkyl; and    -   iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle        and heteroaryl is optionally substituted with halo, (C₁-C₆)alkyl        or COOH;

each Z¹¹ is independently selected from Z¹⁰, —C(═O)—NH₂,—C(═O)—NH(C₁-C₄)alkyl, —C(═O)—N((C₁-C₄)alkyl)₂, —C(═O)-aryl,—C(═O)-heterocycle and —C(═O)-heteroaryl;

each Z¹² is independently selected from —NO₂, ═NOR_(a), thioxo, aryl,heterocycle, heteroaryl, (C₃-C₇)halocarbocycle, (C₃-C₇)carbocycle,—O(C₃-C₇)carbocycle, —Ohalo(C₃-C₇)carbocycle, —Oaryl, —Oheterocycle,—Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle,—Shalo(C₃-C₇)carbocycle, —Saryl, —Sheterocycle, —Sheteroaryl,—S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)halo(C₃-C₇)carbocycle,—S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SO₂aryl,—SO₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(a), —NR_(a)C(O)R_(b),—C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z¹³ is independently selected from —NO₂, —OH, ═NOR_(a), —SH, —CN,—(C₃-C₇)halocarbocycle, —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl,—O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl, —O(C₃-C₇)carbocycle,—O(C₃-C₇)halocarbocycle, —Oaryl, —Oheteroaryl, —Oheterocycle,—S(C₁-C₆)alkyl, —S(C₂-C₆)alkenyl, —S(C₂-C₆)alkynyl, —S(C₁-C₆)haloalkyl,—S(C₃-C₇)carbocycle, —S(C₃-C₇)halocarbocycle, —Saryl, —Sheteroaryl,—Sheterocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₂-C₆)alkenyl,—S(O)(C₂-C₆)alkynyl, —S(O)(C₁-C₆)haloalkyl, S(O)(C₃-C₇)carbocycle,—S(O)(C₃-C₇)halocarbocycle, —S(O)aryl, —S(O)heteroaryl,—S(O)heterocycle, —SO₂(C₁-C₆)alkyl, —SO₂(C₂-C₆)alkenyl,—SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(C₃-C₇)carbocycle,—SO₂(C₃-C₇)halocarbocycle, —SO₂aryl, —SO₂heteroaryl, —SOz₂heterocycle,—SO₂NR_(c)R_(d), —NR_(c)R_(d), —NR_(a)C(O)R_(a), —NR_(a)C(O)OR_(b),—NR_(a)C(O)NR_(c)R_(d)—NR_(a)SO₂R_(b), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a), —C(O)R_(a),—C(O)OR_(b), —C(O)NR_(c)R_(d), and —OC(O)NR_(c)R_(d), wherein any(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl orheterocycle of Z¹³, either alone or as part of a group, is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen, —OH,—OR_(b), —CN, —NR_(a)C(O)₂R_(b), -heteroaryl, -heterocycle,—Oheteroaryl, —Oheterocycle, —NHheteroaryl, —NHheterocycle, or—S(O)₂NR_(c)R_(d);

each Z¹⁴ is independently selected from —NO₂, ═NOR_(a), —CN,(C₃-C₇)halocarbocycle, —O(C₃-C₇)halocarbocycle, —S(C₃-C₇)halocarbocycle,—S(O)(C₃-C₇)halocarbocycle, —SO₂(C₃-C₇)halocarbocycle,—NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)halocarbocycle, —NR_(a)SO₂Oaryland —OS(O)₂R_(a), wherein any (C₃-C₇)halocarbocycle of Z¹⁴, either aloneor as part of a group, is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b),-heteroaryl, -heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl,—NHheterocycle, or —S(O)₂NR_(c)R_(d);

each R_(a) is independently H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryl(C₁-C₆)alkyl-,heteroaryl or heteroaryl(C₁-C₆)alkyl-, wherein any (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, orheteroaryl of R_(a), either alone or as part of a group, is optionallysubstituted by halogen, OH and cyano;

each R_(b) is independently (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryl(C₁-C₆)alkyl-,heteroaryl or heteroaryl(C₁-C₆)alkyl-, wherein any (C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl,or heteroaryl of R_(b), either alone or as part of a group, isoptionally substituted by halogen, OH and cyano;

R_(c), and R_(d) are each independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, aryl,aryl(C₁-C₆)alkyl-, heterocycle, heteroaryl and heteroaryl(C₁-C₆)alkyl-,wherein any (C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,(C₃-C₇)carbocycle, heterocycle, aryl and heteroaryl of R_(c) or R_(d),either alone or as part of a group, is optionally substituted byhalogen, OH and cyano; or R_(c) and R_(d) together with the nitrogen towhich they are attached form a heterocycle, wherein any heterocycle ofR_(c), and R_(d) together with the nitrogen to which they are attachedis optionally substituted by halogen, OH or cyano;

each R_(e) is independently selected from —OR_(a), (C₁-C₆)alkyl and(C₃-C₇)carbocycle, wherein (C₁-C₆)alkyl and (C₃-C₇)carbocycle aresubstituted by one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹,(C₂-C₆)haloalkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein any(C₂-C₆)haloalkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹, and aryl,heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroarylare substituted by one or more Z⁵;

each R_(f) is independently selected from —R_(g), —OR_(a),—(C₁-C₆)alkyl-Z⁶, —SO₂R_(g), —C(O)R_(g), C(O)OR_(g), and—C(O)NR_(e)R_(g); and

each R_(g) is independently selected from H, —OR_(a), (C₁-C₆)alkyl,(C₃-C₇)carbocycle, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl, heterocycle and heteroaryl, wherein any (C₁-C₆)alkyl,(C₃-C₇)carbocycle, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl, heterocycle or heteroaryl of R_(g) is optionally substituted withone or more Z¹ groups;

or a salt thereof.

The invention also provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable salt thereof, incombination with a pharmaceutically acceptable carrier.

The invention also provides method for treating (e.g. preventing,mediating or inhibiting) the proliferation of the HIV virus, treatingAIDS or delaying the onset of AIDS or ARC symptoms in a mammal (e.g. ahuman), comprising administering a compound of formula I, or apharmaceutically acceptable salt thereof, to the mammal.

The invention also provides a compound of formula I, or apharmaceutically acceptable salt thereof for use in medical therapy(e.g. for use in treating (e.g. preventing, mediating or inhibiting) theproliferation of the HIV virus or AIDS or delaying the onset of AIDS orARC symptoms in a mammal (e.g. a human)).

The invention also provides a compound of formula I, or apharmaceutically acceptable salt thereof for use in the manufacture of amedicament for treating (e.g. preventing, mediating or inhibiting) theproliferation of the HIV virus or AIDS or delaying the onset of AIDS orARC symptoms in a mammal (e.g. a human).

The invention also provides a compound of formula I, or apharmaceutically acceptable salt thereof, for use in the prophylactic ortherapeutic treatment (e.g. prevention, mediation or inhibiting) of theproliferation of the HIV virus or AIDS or for use in the therapeutictreatment of delaying the onset of AIDS or ARC symptoms.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing compounds of formula I or salts thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Alkyl” is hydrocarbon containing normal, secondary or tertiary atoms.For example, an alkyl group can have 1 to 20 carbon atoms (i.e.,(C₁-C₂₀)alkyl), 1 to 10 carbon atoms (i.e., (C₁-C₁₀)alkyl), 1 to 8carbon atoms (i.e., (C₁-C₈)alkyl)or 1 to 6 carbon atoms (i.e., (C₁-C₆alkyl). Examples of suitable alkyl groups include, but are not limitedto, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (t-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃). “Alkyl”also refers to a saturated, branched or straight chain hydrocarbonradical having two monovalent radical centers derived by the removal oftwo hydrogen atoms from the same or two different carbon atoms of aparent alkane. For example, an alkyl group can have 1 to 10 carbon atoms(i.e., (C₁-C₁₀)alkyl), or 1 to 6 carbon atoms (i.e., (C₁-C₆)alkyl) or1-3 carbon atoms (i.e., (C₁-C₃)alkyl). Typical alkyl radicals include,but are not limited to, methylene(—CH₂—), 1,1-ethyl (—CH(CH₃)—),1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—), 1,2-propyl(—CH₂CH(CH₃)—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—),and the like.

“Alkenyl” is a straight or branched hydrocarbon containing normal,secondary or tertiary carbon atoms with at least one site ofunsaturation, i.e. a carbon-carbon, sp² double bond. For example, analkenyl group can have 2 to 20 carbon atoms (i.e., C₂-C₂₀ alkenyl), 2 to8 carbon atoms (i.e., C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e.,C₂-C₆ alkenyl). Examples of suitable alkenyl groups include, but are notlimited to, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂),cyclopentenyl (—C₅H₇), and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a straight or branched hydrocarbon containing normal,secondary or tertiary carbon atoms with at least one site ofunsaturation, i.e. a carbon-carbon, sp triple bond. For example, analkynyl group can have 2 to 20 carbon atoms (i.e., C₂-C₂₀ alkynyl), 2 to8 carbon atoms (i.e., C₂-C₈ alkyne), or 2 to 6 carbon atoms (i.e., C₂-C₆alkynyl). Examples of suitable alkynyl groups include, but are notlimited to, acetylenic (—C≡CH), propargyl (—CH₂C≡CH), and the like.

The term “halo” or “halogen” as used herein refers to fluoro, chloro,bromo and iodo.

The term “haloalkyl” as used herein refers to an alkyl as definedherein, wherein one or more hydrogen atoms are each replaced by a halosubstituent. For example, a (C₁-C₆)haloalkyl is a (C₁-C₆)alkyl whereinone or more of the hydrogen atoms have been replaced by a halosubstituent. Such a range includes one halo substituent on the alkylgroup to complete halogenation of the alkyl group.

The term “aryl” as used herein refers to a single aromatic ring or abicyclic or multicyclic ring. For example, an aryl group can have 6 to20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Arylincludes a phenyl radical or an ortho-fused bicyclic or multicyclicradical having about 9 to 14 atoms in which at least one ring isaromatic (e.g. an aryl fused to one or more aryl or carbocycle). Suchbicyclic or multicyclic rings may be optionally substituted with one ormore (e.g. 1, 2 or 3) oxo groups on any carbocycle portion of thebicyclic or multicyclic ring. It is to be understood that the point ofattachment of a bicyclic or multicyclic radical, as defined above, canbe at any position of the ring including an aryl or a carbocycle portionof the ring. Typical aryl groups include, but are not limited to,phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, andthe like.

“Arylalkyl” refers to an alkyl radical as defined herein in which one ofthe hydrogen atoms bonded to a carbon atom is replaced with an arylradical as described herein (i.e., an aryl-alkyl-moiety). The alkylgroup of the “arylalkyl” is typically 1 to 6 carbon atoms (i.e.aryl(C₁-C₆)alkyl). Arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 1-phenylpropan-1-yl, naphthylmethyl,2-naphthylethan-1-yl and the like.

The term “heteroaryl” as used herein refers to a single aromatic ring ora multiple condensed ring. The term includes single aromatic rings offrom about 1 to 6 carbon atoms and about 1-4 heteroatoms selected fromthe group consisting of oxygen, nitrogen and sulfur in the rings. Thesulfur and nitrogen atoms may also be present in an oxidized formprovided the ring is aromatic. Such rings include but are not limited topyridyl, pyrimidinyl, oxazolyl or furyl. The term also includes multiplecondensed ring systems (e.g. ring systems comprising 2 or 3 rings)wherein a heteroaryl group, as defined above, can be fused with one ormore heteroaryls (e.g. naphthyridinyl), carbocycles (e.g.5,6,7,8-tetrahydroquinolyl) or aryls (e.g. indazolyl) to form a multiplecondensed ring. Such multiple condensed rings may be optionallysubstituted with one or more (e.g. 1, 2 or 3) oxo groups on thecarbocycle portions of the condensed ring. It is to be understood thatthe point of attachment of a heteroaryl multiple condensed ring, asdefined above, can be at any position of the ring including aheteroaryl, aryl or a carbocycle portion of the ring. Exemplaryheteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl,oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl,isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl,quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyland thianaphthenyl.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring or a multiple condensedring system. The term includes single saturated or partially unsaturatedring (e.g. 3, 4, 5, 6 or 7-membered ring) from about 1 to 6 carbon atomsand from about 1 to 3 heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur in the ring. The ring may be substitutedwith one or more (e.g. 1, 2 or 3) oxo groups and the sulfur and nitrogenatoms may also be present in their oxidized forms. Such rings includebut are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl. Theterm also includes multiple condensed ring systems (e.g. ring systemscomprising 2 or 3 rings) wherein a heterocycle group (as defined above)can be connected to two adjacent atoms (fused heterocycle) with one ormore heterocycles (e.g. decahydronapthyridinyl), heteroaryls (e.g.1,2,3,4-tetrahydronaphthyridinyl), carbocycles (e.g. decahydroquinolyl)or aryls. It is to be understood that the point of attachment of aheterocycle multiple condensed ring, as defined above, can be at anyposition of the ring including a heterocycle, heteroaryl, aryl or acarbocycle portion of the ring. Exemplary heterocycles include, but arenot limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl,tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl,dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl and 1,4-benzodioxanyl.

The term “bridged-heterocycle” as used herein refers to a 4, 5, 6, 7 or8-membered heterocycle as defined herein connected at two non-adjacentatoms of the 4, 5, 6, 7 or 8-membered heterocycle with one or more (e.g.1 or 2) 3, 4, 5 or 6-membered heterocycles or a (C₃-C₇)carbocycles asdefined herein. Such bridged-heterocycles include bicyclic and tricyclicring systems (e.g. 2-azabicyclo[2.2.1]heptane and4-azatricyclo[4.3.1.1^(3,8)]undecane).

The term “spiro-heterocycle” as used herein refers to a 3, 4, 5, 6, 7 or8-membered heterocycle as defined herein connected to one or more (e.g.1 or 2) single atoms of the 3, 4, 5, 6, 7 or 8-membered heterocycle withone or more (e.g. 1 or 2) 3, 4, 5, 6-membered heterocycles or a(C₃-C₇)carbocycles as defined herein. Such spiro-heterocycles includebicyclic and tricyclic ring systems (e.g.1,4-dioxaspiro[4.5]dec-7-enyl).

The term “macroheterocycle” as used herein refers to a saturated orpartially unsaturated 8, 9, 10, 11 or 12-membered ring comprising about5 to 11 carbon atoms and about 1 to 3 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur in the ring which may beoptionally fused at two adjacent atoms of the macroheterocycle to one ormore (e.g. 1, 2 or 3) aryls, carbocycles, heteroaryls or heterocycles.The macroheterocycle may be substituted with one or more (e.g. 1, 2 or3) oxo groups and the sulfur and nitrogen atoms may also be present intheir oxidized forms.

“Heteroarylalkyl” refers to an alkyl radical as defined herein in whichone of the hydrogen atoms bonded to a carbon atom is replaced with aheteroaryl radical as described herein (i.e., aheteroaryl-alkyl-moiety). The alkyl group of the “heteroarylalkyl” istypically 1 to 6 carbon atoms (i.e. heteroaryl(C₁-C₆)alkyl).

Heteroarylalkyl groups include, but are not limited to heteroaryl-CH₂—,heteroaryl-CH(CH₃)—, heteroaryl-CH₂CH₂—, 2-(heteroaryl)ethan-1-yl, andthe like, wherein the “heteroaryl” portion includes any of theheteroaryl groups described above. One skilled in the art will alsounderstand that the heteroaryl group can be attached to the alkylportion of the heteroarylalkyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. Examples of heteroarylalkyls include by way ofexample and not limitation 5-membered sulfur, oxygen, and/or nitrogencontaining heteroaryls such as thiazolylmethyl, 2-thiazolylethan-1-yl,imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-memberedsulfur, oxygen, and/or nitrogen containing heteroaryls suchpyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

“Heterocyclylalkyl” refers to an alkyl radical as defined herein inwhich one of the hydrogen atoms bonded to a carbon atom is replaced witha heterocyclyl radical as described herein (i.e., aheterocyclyl-alkyl-moiety). The alkyl group of the “heterocyclylalkyl”is typically 1 to 6 carbon atoms (i.e. heterocyclyl(C₁-C₆)alkyl).Typical heterocyclylalkyl groups include, but are not limited toheterocyclyl-CH₂—, heterocyclyl-CH(CH₃)—, heterocyclyl-CH₂CH₂—,2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl”portion includes any of the heterocyclyl groups described above. Oneskilled in the art will also understand that the heterocyclyl group canbe attached to the alkyl portion of the heterocyclyl alkyl by means of acarbon-carbon bond or a carbon-heteroatom bond, with the proviso thatthe resulting group is chemically stable. Examples of heterocyclylalkylsinclude by way of example and not limitation 5-membered sulfur, oxygen,and/or nitrogen containing heterocycles such tetrahydrofuranylmethyl andpyrroldinylmethyl, etc., and 6-membered sulfur, oxygen, and/or nitrogencontaining heterocycles such as piperidinylmethyl, piperazinylmethyl,morpholinylmethyl, etc.

The term “carbocycle” or “carbocyclyl” refers to a saturated (i.e.,cycloalkyl) or partially unsaturated (e.g., cycloalkenyl,cycloalkadienyl, etc.) ring having 3 to 7 carbon atoms as a monocycle ora multicyclic ring system. In one embodiment the carbocycle is amonocycle comprising 3-6 ring carbons (i.e. (C₁-C₆)carbocycle).Carbocycle includes multicyclic carbocycles have 7 to 12 carbon atoms asa bicycle, and up to about 20 carbon atoms as a polycycle provided thatthe largest single ring of a multicyclic carbocycle is 7 carbon atoms.The term “spiro-bicyclic carbocycle” refers to a carbocycle bicyclicring system wherein the rings of the bicyclic ring system are connectedto a single carbon atom (e.g. spiropentane, spiro[4,5]decane,spiro[4.5]decane, etc). The term “fused-bicyclic carbocycle” refers to acarbocycle bicyclic ring system wherein the rings of the bicyclic ringsystem are connected to two adjacent carbon atoms such as abicyclo[4,5], [5,5], [5,6] or [6,6]system, or 9 or 10 ring atomsarranged as a bicyclo[5,6] or [6,6]system (e.g. decahydronaphthalene,norsabinane, norcarane). The term “bridged-bicyclic carbocycle” refersto a carbocycle bicyclic ring system wherein the rings of the bicyclicring system are connected to two non-adjacent carbon atoms (e.g.norbornane, bicyclo[2.2.2]octane, etc). The “carbocycle” or“carbocyclyl” may be optionally substituted with one or more (e.g. 1, 2or 3) oxo groups. Non-limiting examples of monocyclic carbocyclesinclude cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl and 1-cyclohex-3-enyl.

The term “halocarbocycle” as used herein refers to a carbocycle asdefined herein, wherein one or more hydrogen atoms are each replaced bya halo substituent. For example, (C₃-C₇)halocarbocycle is a(C₃-C₇)carbocycle wherein one or more of the hydrogen atoms have beenreplaced by a halo substituent. Such a range includes one halosubstituent on the carbocycle group to complete halogenation of thecarbocycle group.

The term “macrocarbocycle” as used herein refers to a saturated orpartially unsaturated 8, 9, 10, 11 or 12-membered ring comprising 8 to12 carbon atoms which may be optionally fused at two adjacent atoms ofthe macrocarbocycle to one or more (e.g. 1, 2 or 3) aryls, carbocycles,heteroaryls or heterocycles. The macrocarbocycle may be substituted withone or more (e.g. 1, 2 or 3) oxo groups.

“Carbocyclylalkyl” refers to an alkyl radical as defined herein in whichone of the hydrogen atoms bonded to a carbon atom is replaced with acarbocyclyl radical as described herein (i.e., acarbocyclyl-alkyl-moiety). The alkyl group of the “carbocyclylalkyl” istypically 1 to 6 carbon atoms (i.e. carbocyclyl(C₁-C₆)alkyl). Typicalcarbocyclyl alkyl groups include, but are not limited tocarbocyclyl-CH₂—, carbocyclyl-CH(CH₃)—, carbocyclyl-CH₂CH₂—,2-(carbocyclyl)ethan-1-yl, and the like, wherein the “carbocyclyl”portion includes any of the carbocyclyl groups described above.

It is to be understood that when a variable is substituted, for exampleas described by the phrase “(C₁-C₆)alkyl, either alone or as part of agroup, is optionally substituted”, the phrase means that the variable(C₁-C₆)alkyl can be substituted when it is alone and that it can also besubstituted when the variable “(C₁-C₆)alkyl” is part of a larger groupsuch as for example an aryl(C₁-C₆)alkyl or a—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle group. Similarly, whenstated, other variables (e.g. (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, aryl,heteroaryl, heterocycle, etc. . . . ) can also be substituted “eitheralone or as part of a group.”

It is to be understood that certain variables of formula I that connecttwo chemical groups may be oriented in either direction. Thus, for the Xgroup of formula I (e.g. O, —C(O)—, —C(O)O—, —S—, —S(O)—, —SO₂—,—(C₁-C₆)alkylO—, —(C₁-C₆)alkylC(O)—, —(C₁-C₆)alkylC(O)O—,—(C₁-C₆)alkylS—, —(C₁-C₆)alkylS(O)— and —(C₁-C₆)alkylSO₂—) certainvalues of X that are not symmetric can be oriented in either direction.For example, the —C(O)O—, can be oriented as either —C(O)O— or —OC(O)—,relative to the groups it connects.

One skilled in the art will recognize that substituents and othermoieties of the compounds of formula I should be selected in order toprovide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of formula Iwhich have such stability are contemplated as falling within the scopeof the present invention.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity). The word “about” may also be representedsymbolically by “˜” in the context of a chemical measurement (e.g. ˜50mg or pH ˜7).

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers or axesof chirality and whose molecules are not mirror images of one another.Diastereomers typically have different physical properties, e.g.,melting points, boiling points, spectral properties, and reactivities.Mixtures of diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Certain compounds of the invention can exist as atropisomers. Forexample, it has been discovered that atropisomers exist for certainsubstituents at the R⁴ position of formula I as marked by an asterisk inthe formula below.

The chirality that results from the atropisomers at the asteriskposition is a feature of certain compounds of the invention.Accordingly, the invention includes all atropisomers of compounds of theinvention including mixtures of atropisomers and well as mixtures thatare enriched in an atropisomer as well as single atropisomers, whichmixtures or compounds possess the useful properties described herein.

In one embodiment, the compounds of the invention of formula I are atleast 60% a single atropisomer for the R⁴ substituent at the asteriskposition. In another embodiment, the compounds of the invention offormula I are at least 70% a single atropisomer for the R⁴ substituentat the asterisk position. In another embodiment, the compounds of theinvention of formula I are at least 80% a single atropisomer for the R⁴substituent at the asterisk position. In another embodiment, thecompounds of the invention of formula I are at least 90% a singleatropisomer for the R⁴ substituent at the asterisk position. In anotherembodiment, the compounds of the invention of formula I are at least 95%a single atropisomer for the R⁴ substituent at the asterisk position. Inone embodiment the stereochemistry for the R⁴ substituent at the carbonmarked with an asterisk as shown above for Formula I is the (R)stereochemistry. In another embodiment the stereochemistry for the R⁴substituent at the carbon marked with an asterisk as shown above forFormula I is the (S) stereochemistry.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes (D and L) or (Rand S) are used to denote the absolute configuration of the moleculeabout its chiral center(s). The prefixes d and 1 or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with (−) or 1 meaning that the compound is levorotatory. Acompound prefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g., alcohols, bephysiologically acceptable, although in general it is more desirable ifthe products are pharmacologically innocuous.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. PGs do not need to be, and generally are not, the same if thecompound is substituted with multiple PG. In general, PG will be used toprotect functional groups such as carboxyl, hydroxyl, thio, or aminogroups and to thus prevent side reactions or to otherwise facilitate thesynthetic efficiency. The order of deprotection to yield freedeprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) include“ether- or ester-forming groups”. Ether- or ester-forming groups arecapable of functioning as chemical protecting groups in the syntheticschemes set forth herein. However, some hydroxyl and thio protectinggroups are neither ether-nor ester-forming groups, as will be understoodby those skilled in the art, and are included with amides, discussedbelow.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,New York, 1994), which is incorporated by reference in its entiretyherein. In particular Chapter 1, Protecting Groups: An Overview, pages1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3,Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl ProtectingGroups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages155-184. For protecting groups for carboxylic acid, phosphonic acid,phosphonate, sulfonic acid and other protecting groups for acids seeGreene as set forth below.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiralcarbon or phosphorus atoms. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures can be separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

Examples of pharmaceutically acceptable salts of the compounds of theinvention include salts derived from an appropriate base, such as analkali metal (for example, sodium), an alkaline earth metal (forexample, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl).Pharmaceutically acceptable salts of a hydrogen atom or an amino groupinclude for example salts of organic carboxylic acids such as acetic,benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric,phosphoric and sulfamic acids. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein X isindependently selected from H or a C₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will typically be pharmaceutically acceptable, i.e. they willbe salts derived from a physiologically acceptable acid or base.However, salts of acids or bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a compound of formula I or another compound of theinvention. All salts, whether or not derived from a physiologicallyacceptable acid or base, are within the scope of the present invention.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines, or to acidic groups. Finally,it is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the natural orunnatural amino acids are suitable, especially the naturally-occurringamino acids found as protein components, although the amino acidtypically is one bearing a side chain with a basic or acidic group,e.g., lysine, arginine or glutamic acid, or a neutral group such asglycine, serine, threonine, alanine, isoleucine, or leucine.

Specific values listed below for radicals, substituents, and ranges inthe embodiments of the invention are for illustration only; they do notexclude other defined values or other values within defined ranges forthe radicals and substituents.

Isotopes

It is understood by one skilled in the art that this invention alsoincludes any compound claimed that may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D). As a non-limiting example,a —CH₃ group may be substituted with —CD₃.

Compounds of Formula I.

A specific group of compounds of formula I are compounds of formula Ia.

Another specific group of compounds of formula I are compounds offormula Ib.

Another specific group of compounds of formula I are compounds offormula Ic.

Another specific group of compounds of formula I are compounds offormula Id.

Another specific group of compounds of formula I are compounds offormula Ie.

Another specific group of compounds of formula I are compounds offormula If.

Another specific group of compounds of formula I are compounds offormula Ig.

Another specific group of compounds of formula I are compounds offormula Ih.

Another specific group of compounds of formula I are compounds offormula Ii.

Another specific group of compounds of formula I are compounds offormula Ij.

Another specific group of compounds of formula I are compounds offormula Ik.

Another specific group of compounds of formula I are compounds offormula Im.

Another specific group of compounds of formula I are compounds offormula In.

Another specific group of compounds of formula I are compounds offormula Io.

Specific values listed below are values for compounds of formula I aswell as the compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij,Ik, Im, In and Io.

A specific group of compounds of formula I are compounds wherein atleast one of R¹, R², R³, R³, R⁴, R⁵, R⁶, R⁷, or R⁸ is selected fromR^(1b), R^(2b), R^(3b), R^(3b′), R^(4b), R^(5b), R^(6b), R^(7b) andR^(8b).

Another specific group of compounds of formula I are compounds whereinat least two of R¹, R², R³, R^(3′), R⁴, R⁵, R⁶, R⁷, or R⁸ are selectedfrom R^(1b), R^(2b), R^(3b), R^(3b′), R^(4b), R^(5b), R^(6b), R^(7b) andR^(8b).

Another specific group of compounds of formula I are compounds whereinat least three of R¹, R², R³, R^(3′), R⁴, R⁵, R⁶, R⁷, or R⁸ areindependently selected from R^(1b), R^(2b), R^(3b), R^(3b′), R^(4b),R^(5b), R^(6b), R^(7b) and R^(8b).

Another specific group of compounds of formula I are compounds whereinat least four of R¹, R², R³, R^(3′), R⁴, R⁵, R⁶, R⁷, or R⁸ are selectedfrom R^(1b), R^(2b), R^(3b), R^(3b′), R^(4b), R^(5b), R^(6b), R^(7b) andR^(8b).

Another specific group of compounds of formula I wherein at least fiveof R¹, R², R³, R^(3′), R⁴, R⁵, R⁶, R⁷, or R⁸ are selected from R^(1b),R^(2b), R^(3b), R^(3b′), R^(4b), R^(5b), R^(6b), R^(7b) and R^(8b).

Another specific group of compounds of formula I wherein at least six ofR¹, R², R³, R^(3′), R⁴, R⁵, R⁶, R⁷, or R⁸ are independently selectedfrom R^(1b), R^(2b), R^(3b), R^(3b′), R^(4b), R^(5b), R^(6b), R^(7b), orR^(8b).

Another specific group of compounds of formula I wherein at least sevenof R¹, R², R³, R^(3′), R⁴, R⁵, R⁶, R⁷, or R⁸ are independently selectedfrom R^(1b), R^(2b), R^(3b), R^(3b′), R^(4b), R^(5b), R^(6b), R^(7b) andR^(8b).

Another specific group of compounds of formula I wherein at least eightof R¹, R², R³, R^(3′), R⁴, R⁵, R⁶, R⁷, or R⁸ are independently selectedfrom Rtb, R^(2b), R^(3b), R^(3b) R^(4b), R^(5b), R^(6b), R^(7b) andR^(8b).

Another specific group of compounds of formula I wherein R¹, R², R³,R^(3′), R⁴, R⁵, R⁶, R⁷ and R⁸are R^(1b), R^(2b), R^(3b), R^(3b′),R^(4b), R^(5b), R^(6b), R^(7b) and R^(8b).

A specific value for R³ is R^(3b)

A specific value for R^(3b) is —OC(CH₃)₂CH₂OH, —OC(CH₃)₂CH₂OH,—O(C₁-C₆)alkyl-O—C(O)—NH₂, —O(C₁-C₆)alkyl-O—C(O)—N(CH₃)₂ or—O(C₁-C₆)alkyl-O—C(O)—NH(phenyl).

Another specific value for R^(3b) is —(C₁-C₆)alkylOH or—O(C₁-C₆)alkyl-O—C(O)—NR_(c)R_(d).

Another specific value for R³ is R^(3a)

A specific value for R^(3a) is (C₁-C₆)alkyl, (C₂-C₆)alkenyl or—O(C₁-C₆)alkyl, wherein any (C₁-C₆)alkyl or (C₂-C₆)alkenyl of R^(3a) isoptionally substituted with one or more groups selected from—O(C₁-C₆)alkyl, halo, oxo and —CN.

Another specific value for R^(3a) is —OC(CH₃).

A specific value for R^(3′) is R^(3b′).

A specific value for R^(3b′) is (C₁-C₆)alkyl or —O(C₁-C₆)alkyl.

A specific value for R^(3′) is R^(3a′.)

A specific value for R^(3a′) is H.

A specific group of compounds of formula I are compounds wherein R^(3b)and R^(3b′) together with the carbon to which they are attached form a(C₃-C₇)carbocycle or heterocycle, wherein the (C₃-C₇)carbocycle orheterocycle is optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR^(3b) and R^(3b′) together with the carbon to which they are attachedform a (C₃-C₇)carbocycle or a 4, 5 or 6-membered heterocycle, whereinthe (C₃-C₇)carbocycle or the 4, 5 or 6-membered heterocycle isoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR^(3b) and R^(3b′) together with the carbon to which they are attachedform a (C₄-C₆)carbocycle or a 5 or 6-membered heterocycle, wherein the(C₄-C₆)carbocycle or the 5 or 6-membered heterocycle is optionallysubstituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR^(3b) and R^(3b′) together with the carbon to which they are attachedform a 5 or 6-membered heterocycle, wherein the 5 or 6-memberedheterocycle is optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR^(3b) and R^(3b′) together with the carbon to which they are attachedform a tetrahydropyran or tetrahydrofuran optionally substituted withone or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR^(3b) and R^(3b′) together with the carbon to which they are attachedform:

each of which is optionally substituted with one or more Z¹ groups; andwherein “*” denotes the point of attachment to the carbon of thecompound of formula I.

A specific value for R⁴ is R^(4b)

A specific value for R^(4b) is (C₁-C₆)alkyl, (C₂-C₆)alkenyl or(C₂-C₆)alkynyl, wherein (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynylare each optionally substituted with one or more Z¹ groups.

Another specific value for R^(4b) is:

optionally substituted with one or more Z¹ groups.

Another specific value for R^(4b) is (C₃-C₇)carbocycle, wherein(C₃-C₇)carbocycle is optionally substituted with one or more Z¹ groups,or wherein two Z¹ groups together with the atom or atoms to which theyare attached optionally form a (C₃-C₆)carbocycle or 5-6-memberedheterocycle.

Another specific value for R^(4b) is:

each of which is optionally substituted with one or more Z¹ groups.

Another specific value for R^(4b) is aryl, heterocycle or heteroaryl,wherein aryl, heterocycle and heteroaryl are each independentlysubstituted with one or more Z⁷ groups and optionally substituted withone or more Z¹ groups.

Another specific value for R^(4b) is:

Another specific value for R⁴ is R^(4a).

A specific value for R^(4a) is:

A specific group of compounds of formula I are compounds wherein R⁴ andR³ together with the atoms to which they are attached form amacroheterocycle or a macrocarbocycle, wherein any macroheterocycle ormacrocarbocycle of R⁴ and R³-together with the atoms to which they areattached may be optionally substituted with one or more Z¹ groups; andR^(3′) is H, (C₁-C₆)alkyl or —O(C₁-C₆)alkyl.

Another specific value for R^(3′) is H.

Another specific group of compounds of formula I are compounds whereinR⁴ and R³ together with the atoms to which they are attached form themacroheterocycle or a macrocarbocycle further fused to a Z group:

wherein:

Z is aryl, heteroaryl or (C₃-C₆)carbocycle;

n3 is 2, 3 or 4; and

W¹ and W² are each independently O, NH or CH₂, and

wherein “*” denotes the R⁴ point of attachment of the macroheterocycleor macrocarbocycle to the compound of formula I and “**” denotes the R³point of attachment of the macroheterocycle or macrocarbocycle to thecompound of formula I, and wherein the macroheterocycle or amacrocarbocycle is optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds wherein,R⁴ and R³ together with the atoms to which they are attached form themacroheterocycle:

-   -   wherein:

n1 is 3 or 4; n2 is 2, 3 or 4; n3 is 2, 3 or 4; W is O, NH orN(C₁-C₄)alkyl; and wherein “*” denotes the R⁴ point of attachment of themacroheterocycle to the compound of formula I and “**” denotes the R³point of attachment of the macroheterocycle to the compound of formulaI, and wherein the macroheterocycle or a macrocarbocycle is optionallysubstituted with one or more Z¹ groups

A specific value for R¹ is R^(1b)

Another specific value R¹ is R^(1a).

A specific value for R^(1a) is H or —CH₃.

A specific value for R² is R^(2b).

Another specific value R² is R^(2a)

A specific value for R^(2a) is H or —CH₃.

A specific value for R⁵ is R^(5b)

Another specific value for R⁵ is R^(5a)

A specific value for R^(5a) is H.

A specific value for R⁶ is R^(6b).

Another specific value for R⁶ is R^(6a).

A specific value for R^(6a) is H.

A specific value for R⁷ is R^(7b).

Another specific value for R⁷ is R^(7a).

A specific value for R^(7a) is H, —CH₃ or halogen.

A specific value for R⁸ is R^(8b).

Another specific value for R⁸ is R^(8a).

Another specific value for R^(8a) is H.

A specific group of compounds of formula I are compounds wherein R^(4b)is selected from;

a) (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein(C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) (C₃-C₁₄)carbocycle, wherein (C₃-C₁₄)carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups;

c) Spiro-heterocycle and bridged-heterocycle, wherein spiro-heterocycleand bridged-heterocycle are each optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

d) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle andheteroaryl are each independently substituted with one or more Z⁷ groupsand optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups; or

Another specific group of compounds of formula I are compounds whereinR^(4b) is selected from;

a) (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein(C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) (C₃-C₁₄)carbocycle, wherein (C₃-C₁₄)carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups, whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle; and

c) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle andheteroaryl are each independently substituted with one or more Z⁷ groupsand optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups; or

Another specific group of compounds of formula I are compounds whereinR^(4b) is selected from;

a) (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein(C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) (C₃-C₁₄)carbocycle, wherein (C₃-C₁₄)carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

c) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle andheteroaryl are each independently substituted with one or more Z⁷ groupsand optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups.

Another specific group of compounds of formula I are compounds whereinR³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl or —O(C₁-C₆)alkyl, wherein any(C₁-C₆)alkyl or (C₂-C₆)alkenyl of R³ is optionally substituted with oneor more groups selected from —O(C₁-C₆)alkyl, halo, oxo and —CN, andwherein R^(3′) is H.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle andheteroaryl are each optionally substituted with one or more groups eachindependently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH,—S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein(C₁-C₆)alkyl is optionally substituted with hydroxy, —O(C₁-C₆)alkyl,cyano or oxo;

b) (C₃-C₁₄)carbocycle, wherein (C₃-C₁₄)carbocycle is optionallysubstituted with one or more Z¹ groups, wherein two Z¹ groups togetherwith the atom or atoms to which they are attached optionally form a(C₃-C₇)carbocycle or heterocycle; and

c) aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl andfused-heterocycle are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) aryl, heterocycle and heteroaryl, wherein aryl, heterocycle andheteroaryl are each optionally substituted with one or more groups eachindependently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH,—S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein(C₁-C₆)alkyl is optionally substituted with hydroxy, —O(C₁-C₆)alkyl,cyano or oxo; and

b) aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl andfused-heterocycle are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) heterocycle and heteroaryl, wherein heterocycle and heteroaryl areeach optionally substituted with one or more groups each independentlyselected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl isoptionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and

b) heteroaryl and fused-heterocycle, wherein heteroaryl andfused-heterocycle are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) heterocycle, wherein heterocycle is optionally substituted with oneor more groups each independently selected from halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH,—O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and—N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted withhydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and

b) fused-heterocycle, wherein fused-heterocycle is substituted with oneor more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) bicyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclicheterocycle, bicyclic heteroaryl and tricyclic heteroaryl, wherein anybicyclic aryl, tricyclic aryl, bicyclic heterocycle, tricyclicheterocycle, bicyclic heteroaryl and tricyclic heteroaryl, is optionallysubstituted with one or more groups each independently selected fromhalo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and—N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted withhydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and

b) bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, tricyclicheteroaryl bicyclic fused-heterocycle, and tricyclic fused-heterocycle,wherein bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, tricyclicheteroaryl bicyclic fused-heterocycle and tricyclic fused-heterocycleare each independently substituted with one or more Z⁷ groups andoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) bicyclic heterocycle and tricyclic heterocycle, wherein bicyclicheterocycle and tricyclic heterocycle are each optionally substitutedwith one or more groups each independently selected from halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH,—O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and—N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted withhydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and

b) bicyclic fused-heterocycle and tricyclic fused-heterocycle whereinbicyclic fused-heterocycle and tricyclic fused-heterocyclefused-heterocycle are each substituted with one or more Z⁷ groups andoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) bicyclic heterocycle, tricyclic heterocycle, bicyclic heteroaryl andtricyclic heteroaryl wherein bicyclic heterocycle, tricyclicheterocycle, bicyclic heteroaryl and tricyclic heteroaryl are eachoptionally substituted with one or more groups each independentlyselected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl isoptionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and

b) bicyclic fused-heterocycle and tricyclic fused-heterocycle, whereinbicyclic fused-heterocycle and tricyclic fused-heterocyclefused-heterocycle are each substituted with one or more Z⁷ groups andoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) tricyclic heterocycle, wherein tricyclic heterocycle is optionallysubstituted with one or more groups each independently selected fromhalo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,—OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and—N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted withhydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and

b) tricyclic fused-heterocycle, wherein tricyclic fused-heterocyclefused-heterocycle is substituted with one or more Z⁷ groups andoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) (C₃-C₁₄)carbocycle, wherein (C₃-C₁₄)carbocycle is optionallysubstituted with one or more Z¹ groups, wherein two Z¹ groups togetherwith the atom or atoms to which they are attached optionally form a(C₃-C₇)carbocycle or heterocycle; and

b) aryl, heteroaryl and fused-heterocycle, wherein aryl, heteroaryl andfused-heterocycle are each independently substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from aryl, heteroaryl and fused-heterocycle, whereinaryl, heteroaryl and fused-heterocycle are each independentlysubstituted with one or more Z⁷ groups and optionally substituted withone or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from fused-heterocycle, wherein fused-heterocycle issubstituted with one or more Z⁷ groups and optionally substituted withone or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from bicyclic aryl, tricyclic aryl, bicyclic heteroaryl,tricyclic heteroaryl, bicyclic fused-heterocycle and tricyclicfused-heterocycle, wherein bicyclic aryl, tricyclic aryl, bicyclicheteroaryl, tricyclic heteroaryl, bicyclic fused-heterocycle, andtricyclic fused-heterocycle are each independently substituted with oneor more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from bicyclic fused-heterocycle and tricyclicfused-heterocycle, wherein bicyclic fused-heterocycle and tricyclicfused-heterocycle fused-heterocycle are each substituted with one ormore Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is tricyclic fused-heterocycle, wherein tricyclic fused-heterocyclefused-heterocycle is substituted with one or more Z⁷ groups andoptionally substituted with one or more Z¹ groups.

A specific value for Z¹⁰ is:

-   -   i) halo, (C₁-C₆)haloalkyl; or    -   ii) (C₁-C₆)alkyl optionally substituted with —OH,        —O—(C₁-C₆)haloalkyl.

Another specific value for Z¹⁰ is halo.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from heteroaryl and fused-heterocycle, wherein heteroaryland fused-heterocycle are each independently substituted with one ormore Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is fused-heterocycle, wherein fused-heterocycle is substituted withone or more Z⁷ groups and optionally substituted with one or more Z¹groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from bicyclic aryl, tricyclic aryl, bicyclic heteroaryl,tricyclic heteroaryl bicyclic fused-heterocycle, and tricyclicfused-heterocycle, wherein bicyclic aryl, tricyclic aryl, bicyclicheteroaryl, tricyclic heteroaryl bicyclic fused-heterocycle andtricyclic fused-heterocycle are each independently substituted with oneor more Z⁷ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from bicyclic fused-heterocycle and tricyclicfused-heterocycle wherein bicyclic fused-heterocycle and tricyclicfused-heterocycle fused-heterocycle are each substituted with one ormore Z⁷ groups and optionally substituted with one or more Z groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from tricyclic heterocycle, wherein tricyclic heterocycleis optionally substituted with one or more groups each independentlyselected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl isoptionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from tricyclic fused-heterocycle, wherein tricyclicfused-heterocycle fused-heterocycle is substituted with one or more Z⁷groups and optionally substituted with one or more Z¹ groups.

Another specific value for R⁴ is:

Another specific value for R⁴ is:

Another specific value for R⁴ is:

Another specific value for R⁴ is:

Another specific value for R⁴ is:

Another specific value for R⁴ is:

Another specific value for R⁴ is:

Another specific value for R⁴ is:

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle andheteroaryl is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) groups each independently selected from halo, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH,—O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and—N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted withhydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and

b) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle, andbridged-heterocycle, wherein aryl, heteroaryl, spiro-heterocycle,fused-heterocycle and bridged-heterocycle are each independentlysubstituted with one or more Z⁷ groups and optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from aryl, heteroaryl, spiro-heterocycle,fused-heterocycle, and bridged-heterocycle, wherein aryl, heteroaryl,spiro-heterocycle, fused-heterocycle and bridged-heterocycle are eachindependently substituted with one or more Z⁷ groups and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁴ is selected from:

a) heterocycle, wherein any heterocycle is optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) groups each independently selectedhalo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl; and

b) fused-heterocycle, wherein fused-heterocycle is substituted with oneor more Z⁷ groups and optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups.

Another specific value for R⁴ is heterocycle.

Another specific group of compounds of formula I are compounds whereinthe stereochemistry of the R⁴ substituent relative to the carbon offormula I to which it is attached is the (R) stereochemistry.

Another specific group of compounds of formula I are compounds whereinthe stereochemistry of the R⁴ substituent relative to the carbon offormula I to which it is attached is the (S) stereochemistry.

Another specific group of compounds of formula I are compounds whereinR¹ is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle orheteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein anyaryl, heterocycle or heteroaryl is optionally substituted with one ormore Z¹⁰ groups;

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰,wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle orheteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl heteroaryl and heterocycle, either aloneor as part of a group, is substituted with one or more (e.g. 1, 2, 3, 4or 5) Z^(s)5 groups and optionally substituted with one or more Z¹groups; and

g) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one ormore Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR¹ is selected from:

a) H, halo and (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, cyano, aryl, heterocycle and heteroaryl, wherein anyaryl, heterocycle or heteroaryl is optionally substituted with one ormore Z¹⁰ groups;

c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein any aryl, heterocycle or heteroaryl isoptionally substituted with one or more Z¹⁰ groups;

d) —C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-N(R⁹)R¹⁰, wherein each R⁹ isindependently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, andeach R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹,—SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein any aryl, heterocycle or heteroaryl isoptionally substituted with one or more Z¹⁰ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl and heterocycle, wherein aryl heteroaryl andheterocycle are each substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

g) (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and(C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR¹ is selected from:

a) H, halo and (C₁-C₆)alkyl;

b) cyano, aryl, and heteroaryl, wherein any aryl or heteroaryl isoptionally substituted with one or more Z¹⁰ groups;

c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein any aryl, heterocycle or heteroaryl isoptionally substituted with one or more Z¹⁰ groups;

d) —C(═O)—N(R⁹)R¹ and —(C₁-C₆)alkyl-N(R⁹)R¹⁰, wherein each R⁹ isindependently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, andeach R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹,—SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein any aryl, heterocycle or heteroaryl isoptionally substituted with one or more Z¹⁰ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) aryl and heteroaryl, wherein aryl and heteroaryl are each substitutedwith one or more Z⁵ groups and optionally substituted with one or moreZ¹ groups.

Another specific group of compounds of formula I are compounds whereinR¹ is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z^(I) groups;

b) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle; wherein any aryl heteroaryl and heterocycle either aloneor as part of a group, is substituted with one or more (e.g. 1, 2, 3, 4or 5) Z⁵ groups and optionally substituted with one or more Z¹ groups;and

c) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one ormore Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR¹ is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl, heteroaryl and heterocycle, wherein aryl heteroaryl andheterocycle are each substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

c) (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and(C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups.

Another specific value for R¹ is:

Another specific value for R¹ is halo.

Another specific value for R¹ is fluoro.

Another specific value for R¹ is H.

Another specific value for R¹H, halo or (C₁-C₆)alkyl.

Another specific value for R¹ is H or halo.

Another specific group of compounds of formula I are compounds whereinR² is selected from:

a) H, (C₁-C₆)alkyl and —O(C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl,

wherein aryl, heterocycle or heteroaryl are each optionally substitutedwith one or more Z¹¹ groups; and

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹¹ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰,wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl.

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or moreZ⁶ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR² is selected from:

a) (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl and (C₁-C₆)haloalkyl;

c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein aryl, heterocycle or heteroaryl are eachoptionally substituted with one or more Z¹¹ groups;

d) —(C₁-C₆)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selectedfrom H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ isindependently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹, —C(═O)—R¹¹,—C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independentlyselected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) (C₂-C₆)alkenyl, wherein (C₂-C₆)alkenyl is substituted with one ormore Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR² is selected from:

a) (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl and (C₁-C₆)haloalkyl;

c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein aryl, heterocycle or heteroaryl are eachoptionally substituted with one or more Z¹¹ groups; d)—(C₁-C₆)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected fromH, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each Ro¹ is independentlyselected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR and—C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

f) (C₁-C₆)haloalkyl and (C₂-C₆)alkenyl, wherein (C₁-C₆)haloalkyl and(C₂-C₆)alkenyl are each substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR² is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

b) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or moreZ⁶ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR² is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

b) (C₂-C₆)alkenyl, wherein (C₂-C₆)alkenyl is substituted with one ormore

Z⁶ groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR² is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups; and

b) (C₁-C₆)haloalkyl and (C₂-C₆)alkenyl, wherein (C₁-C₆)haloalkyl and(C₂-C₆)alkenyl are each substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups.

Another specific value for R² is:

Another specific value for R² is methyl.

Another specific value for R² is H.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo, (C₁-C₆)alkyl, and (C₁-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle orheteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,heterocycle or heteroaryl of R⁶ is optionally substituted with one ormore Z¹ groups;

d) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ or -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl, heterocycle or heteroaryl, either alone or as part of a group, isoptionally substituted with one or more Z¹ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl heteroaryl and heterocycle either aloneor as part of a group, is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

g) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more Z⁶ groups and optionally substituted with one or moreZ¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo and (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and aryl, wherein any aryl isoptionally substituted with one or more Z¹⁰ groups; c) —(C₁-C₆)alkyl-R¹¹and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,heterocycle or heteroaryl of R⁶ is optionally substituted with one ormore Z¹⁰ groups; d) —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl and—(C₂-C₆)alkynyl-heterocycle, wherein any (C₃-C₇)carbocycle,(C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, as part of a group, isoptionally substituted with one or more Z¹ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

g) (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and(C₂-C₆)alkynyl are each independently substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo, (C₁-C₆)alkyl, and (C₁-C₆)haloalkyl

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle andheteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹ is independently selected from H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,heterocycle and heteroaryl of R⁶ is optionally substituted with one ormore Z¹⁰ groups;

d) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OR_(a), —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a),—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or aspart of a group, is optionally substituted with one or more Z¹ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocyclewherein any aryl, heteroaryl and heterocycle, either alone or as part ofa group, is substituted with one or more Z⁵ groups and optionallysubstituted with one or more Z¹ groups; and

g) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein any (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl is substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo and (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and aryl, wherein any aryl isoptionally substituted with one or more Z¹⁰ groups;

c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ isoptionally substituted with one or more Z¹⁰ groups;

d) —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OR_(a), and —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a),wherein —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OR_(a), and —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a), areoptionally substituted with one or more Z¹ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

g) (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and(C₂-C₆)alkynyl are each independently substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo, (C₁-C₆)alkyl, and (C₁-C₆)haloalkyl

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle andheteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,heterocycle and heteroaryl of R⁶ is optionally substituted with one ormore Z¹⁰ groups; d) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OH, —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a),—(C₃-C₇)carbocycle-Z and -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl, heterocycle and heteroaryl, either alone or as part of a group, isoptionally substituted with one or more Z¹ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocyclewherein any aryl, heteroaryl and heterocycle, either alone or as part ofa group, is substituted with one or more Z⁵ groups and optionallysubstituted with one or more Z¹ groups; and

g) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein any (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl is substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo and (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and aryl, wherein any aryl isoptionally substituted with one or more Z¹⁰ groups; c) —(C₁-C₆)alkyl-R¹¹and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,heterocycle or heteroaryl of R⁶ is optionally substituted with one ormore Z¹⁰ groups;

d) —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OR_(a), and —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a),wherein —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OH, and —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a), areoptionally substituted with one or more Z¹ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

g) (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and(C₂-C₆)alkynyl are each independently substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or aspart of a group, is optionally substituted with one or more Z¹ groups;

b) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

c) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocyclewherein any aryl heteroaryl and heterocycle, either alone or as part ofa group, is substituted with one or more Z⁵ groups and optionallysubstituted with one or more Z¹ groups; and

d) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more Z⁶ groups and optionally substituted with one or moreZ¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo and (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and aryl, wherein any aryl isoptionally substituted with one or more Z¹⁰ groups; c) —(C₁-C₆)alkyl-R¹¹and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,heterocycle or heteroaryl of R⁶ is optionally substituted with one ormore Z¹⁰ groups;

d) —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl and —(C₂-C₆)alkynyl-heterocycle, wherein any(C₃-C₇)carbocycle, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, aspart of a group, is optionally substituted with one or more Z¹ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

g) (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and(C₂-C₆)alkynyl are each independently substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OR_(a), —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a),—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or aspart of a group, is optionally substituted with one or more Z¹ groups;

b) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

c) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocyclewherein any aryl heteroaryl and heterocycle, either alone or as part ofa group, is substituted with one or more Z⁵ groups and optionallysubstituted with one or more Z¹ groups; and

d) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more Z⁶ groups and optionally substituted with one or moreZ¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo and (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and aryl, wherein any aryl isoptionally substituted with one or more Z¹⁰ groups;

c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ isoptionally substituted with one or more Z¹⁰ groups;

d) —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OR_(a) and —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a),wherein any (C₃-C₇)carbocycle, (C₂-C₆)alkynyl, aryl, heterocycle andheteroaryl, as part of a group, is optionally substituted with one ormore Z¹ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

g) (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and(C₂-C₆)alkynyl are each independently substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OH, —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a),—(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any(C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or aspart of a group, is optionally substituted with one or more Z¹ groups;

b) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

c) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocyclewherein any aryl heteroaryl and heterocycle, either alone or as part ofa group, is substituted with one or more Z⁵ groups and optionallysubstituted with one or more Z¹ groups; and

d) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more Z⁶ groups and optionally substituted with one or moreZ¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁶ is selected from:

a) H, halo and (C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and aryl, wherein any aryl isoptionally substituted with one or more Z¹⁰ groups;

c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ isoptionally substituted with one or more Z¹⁰ groups; d)—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₂-C₈)alkynyl-OH and —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a), whereinany (C₃-C₇)carbocycle, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl,as part of a group, is optionally substituted with one or more Z¹groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, wherein aryl is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups; and

g) (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and(C₂-C₆)alkynyl are each independently substituted with one or more Z⁶groups and optionally substituted with one or more Z¹ groups.

Another specific value for R⁶ is:

Another specific value for R⁶ is

Another specific value for R⁶ is H.

Another specific group of compounds of formula I are compounds whereinR⁷ is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle orheteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —S₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰groups;

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰,wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle orheteroaryl is optionally substituted with one or more Z¹⁰ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein aryl, heteroaryl and heterocycle are eachsubstituted with one or more Z⁵ groups and optionally substituted withone or more Z¹ groups;

g) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or moreZ⁶ groups and optionally substituted with one or more Z¹ groups; and

h) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein each (C₁-C₆)alkyl is substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁷ is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

b) (C₃-C₇)cycloalkyl, cyano, aryl and heteroaryl, wherein any aryl, orheteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) —C(═O)—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H,(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independentlyselected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl,heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰groups;

d) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

e) aryl and heteroaryl, wherein aryl and heteroaryl are each substitutedwith one or more Z⁵ groups and optionally substituted with one or moreZ¹ groups;

f) (C₁-C₆)haloalkyl and (C₃-C₇)carbocycle, wherein (C₁-C₆)haloalkyl and(C₃-C₇)carbocycle are each substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups; and

g) —C(O)NR_(e)R_(f).

Another specific group of compounds of formula I are compounds whereinR⁷ is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein aryl, heteroaryl and heterocycle are eachsubstituted with one or more Z⁵ groups and optionally substituted withone or more Z¹ groups;

c) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or moreZ⁶ groups and optionally substituted with one or more Z¹ groups; and

d) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein each (C₁-C₆)alkyl is substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁷ is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl and heteroaryl, wherein aryl and heteroaryl are each substitutedwith one or more Z⁵ groups and optionally substituted with one or moreZ¹ groups;

c) (C₁-C₆)haloalkyl and (C₃-C₇)carbocycle, wherein (C₁-C₆)haloalkyl and(C₃-C₇)carbocycle are each substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups; and

d) —C(O)NR_(e)R_(f).

Another specific group of compounds of formula I are compounds whereinR⁷ is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

b) (C₃-C₇)cycloalkyl, cyano, aryl and heteroaryl, wherein any aryl, orheteroaryl is optionally substituted with one or more Z¹⁰ groups;

c) —O—R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein any aryl, heterocycle orheteroaryl is optionally substituted with one or more Z¹⁰ groups;

d) —C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-N(R⁹)R¹⁰, wherein each R⁹ isindependently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, andeach R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹,—SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl, wherein any aryl, heterocycle or heteroaryl isoptionally substituted with one or more Z¹⁰ groups;

e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

f) aryl and heteroaryl, wherein aryl and heteroaryl are each substitutedwith one or more Z⁵ groups and optionally substituted with one or moreZ¹ groups; and

g) (C₁-C₆)haloalkyl and (C₃-C₇)carbocycle, wherein (C₁-C₆)haloalkyl and(C₃-C₇)carbocycle are each substituted with one or more Z⁶ groups andoptionally substituted with one or more Z¹ groups; and

h) —C(O)NR_(e)R_(f).

Another specific value for R⁷ is:

Another specific value for R⁷ is

Another specific value for R⁷ is

Another specific value for R⁷ is H, halo, (C₁-C₆)alkyl, (C₁-C₆)haloalkyland heteroaryl, wherein heteroaryl is optionally substituted with one ormore Z¹⁰ groups.

Another specific value for R⁷ is H, (C₁-C₆)alkyl or (C₁-C₆)haloalkyl.

Another specific value for R⁷ is H.

Another specific group of compounds of formula I are compounds whereinR⁸ is selected from:

a) halo, nitro and cyano;

b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹ wherein each R¹¹ is independently selected from H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl,heterocycle and heteroaryl are each optionally substituted with one ormore Z¹ groups;

c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰,wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl;

d) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl heteroaryl and heterocycle, either aloneor as part of a group, is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more Z⁶ groups and optionally substituted with one or moreZ¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein any (C₁-C₆)alkyl, as part of a group, is substituted with one ormore Z⁶ groups and optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁸ is selected from:

a) halo and cyano;

b) R¹¹, —O—R¹¹ and —(C₁-C₆)alkyl-R¹¹, wherein each R¹¹ is independentlyselected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl,wherein aryl, heterocycle and heteroaryl are each optionally substitutedwith one or more Z¹ groups;

c) —C(═O)—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H,(C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independentlyselected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl;

d) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

e) aryl and heteroaryl, wherein aryl and heteroaryl are eachindependently substituted with one or more Z⁵ groups and optionallysubstituted with one or more Z¹ groups;

f) (C₂-C₆)alkynyl, wherein (C₂-C₆)alkynyl is substituted with one ormore Z⁶ groups and optionally substituted with one or more Z¹ groups;and

g) —C(O)NR_(e)R_(f).

Another specific group of compounds of formula I are compounds whereinR⁸ is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z¹ groups;

b) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle, wherein any aryl heteroaryl and heterocycle, either aloneor as part of a group, is substituted with one or more Z⁵ groups andoptionally substituted with one or more Z¹ groups;

c) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more Z⁶ groups and optionally substituted with one or moreZ¹ groups; and

d) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f),wherein any (C₁-C₆)alkyl, as part of a group, is substituted with one ormore Z⁶ groups and optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) Z¹ groups.

Another specific group of compounds of formula I are compounds whereinR⁸ is selected from:

a) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more Z^(I) groups;

b) aryl and heteroaryl, wherein aryl and heteroaryl are eachindependently substituted with one or more Z⁵ groups and optionallysubstituted with one or more Z¹ groups;

c) (C₂-C₆)alkynyl, wherein (C₂-C₆)alkynyl is substituted with one ormore Z⁶ groups and optionally substituted with one or more Z¹ groups;and

d) —C(O)NR_(e)R_(f).

Another specific value for R⁸ is.

Another specific value for R⁸ is H.

Another specific value for R⁸ is H, (C₁-C₆)alkyl or halo.

Another specific group of compounds of formula I are compounds whereineach R_(g) is independently selected from —OR_(a), (C₁-C₆)alkyl,(C₃-C₇)carbocycle (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl, heterocycle and heteroaryl, wherein any (C₁-C₆)alkyl,(C₃-C₇)carbocycle —(C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl, heterocycle or heteroaryl of R_(g) is optionally substituted withone or more Z¹ groups.

In one embodiment the compounds of formula I include compounds

wherein:

R¹ is R^(1a) or R^(1b)

R² is R^(2a) or R^(2b)

R³ is R^(3a) or R^(3b)

R^(3′) is R^(3a′) or R^(3b′)

R⁴ is R^(4a) or R^(4b)

R⁵ is R^(5a) or R^(5b)

R⁶ is R^(6a) or R^(6b)

R⁷ is R^(7a) or R^(7b)

R⁸ is R^(8a) or R^(8b)

R^(1a) is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹; wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰; whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; and

each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹,—SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹; wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl; and

wherein any aryl, heterocycle or heteroaryl of R^(1a) is optionallysubstituted with one or more (e.g. 1, 2 or 3) Z¹⁰ groups;

R^(1b) is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₆)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³,—O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³,—SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴,—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl,—(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, —(C₃-C₇)halocarbocycle,—NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ or -halo(C₁-C₆)alkyl-Z³; wherein (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl or heteroaryl are each optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a carbocycle or heterocycle wherein the carbocycle orheterocycle is optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups;

c) (C₁-C₆)alkyl; wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups;

d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl,—X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle; wherein (C₁-C₆)alkyl and(C₁-C₆)haloalkyl are each substituted with one or more Z³ groups andoptionally substituted with one or more Z¹ groups; and wherein(C₂-C₆)alkenyl, (C₂-C₆)alkynyl and (C₃-C₇)carbocycle are eachsubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups andoptionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle; wherein aryl heteroaryl and heterocycle are eachsubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁵ groups andoptionally substituted with one or more Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl; wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one ormore Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f);wherein each (C₁-C₆)alkyl is substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁶ groups and optionally substituted with one or more Z¹ groups;

R^(2a) is selected from:

a) H, (C₁-C₆)alkyl and —O(C₁-C₆)alkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle, heteroaryl, halo, nitro and cyano;

c) C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹; wherein each R¹¹ is independently selected from H,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl and heterocycle and heteroaryl; wherein aryl,heterocycle or heteroaryl are each optionally substituted with one ormore (e.g. 1, 2 or 3) Z¹¹ groups;

d) —OH, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl,—O(C₃-C₇)cycloalkyl, —Oaryl, —Oheterocycle and —Oheteroaryl;

e) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰, and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰; whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; and

each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹,—C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹; wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl;

R^(2b) is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³,—O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³,—SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴,—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³, —(C₃-C₇)halocarbocycle,—NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ or -halo(C₁-C₆)alkyl-Z³; wherein (C₁-C₆)alkyl,—(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl or heteroaryl are each optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle wherein the(C₃-C₆)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl; wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups;

d) —X(C₁-C₆)alkyl, X(C₁-C₆)haloalkyl, X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle; wherein (C₁-C₆)alkyl and (C₁-C₆)haloalkyl areeach substituted with one or more Z³ groups and optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and wherein(C₂-C₆)alkenyl, (C₂-C₆)alkynyl and (C₃-C₇)carbocycle are eachsubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁴ groups andoptionally substituted with one or more Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle; wherein aryl heteroaryl and heterocycle are eachsubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁵ groups andoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl; wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f);wherein each (C₁-C₆)alkyl is substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

R^(3a) is (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl-aryl,—(C₁-C₆)alkyl-heterocycle, —(C₁-C₆)alkyl-heteroaryl, —O(C₁-C₆)alkyl,—O(C₁-C₆)haloalkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,—O(C₃-C₇)cycloalkyl, —Oaryl, —O(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl,—O(C₁-C₆)alkyl-aryl, —O(C₁-C₆)alkyl-heterocycle and—O(C₁-C₆)alkyl-heteroaryl; wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,(C₂-C₆)alkenyl or (C₂-C₆)alkynyl of R^(3a) is optionally substitutedwith one or more (e.g. 1, 2 or 3) groups selected from —O(C₁-C₆)alkyl,halo, oxo and —CN; and wherein any (C₃-C₇)cycloalkyl, aryl, heterocycle,or heteroaryl of R^(3a) is optionally substituted with one or more (e.g.1, 2 or 3) groups selected from (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, halo, oxoand —CN; and R^(3a′) is H;

R^(3b) is —(C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle,—(C₁-C₆)alkylOH, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹²,—(C₁-C₆)alkyl-O—(C₂-C₆)alkenyl-Z¹², —(C₂-C₆)alkyl-O—(C₂-C₆)alkynyl-Z¹²,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z², —(C₁-C₆)alkyl-S—(C₂-C₆)alkenyl-Z¹²,—(C₂-C₆)alkyl-S—(C₂-C₆)alkynyl-Z¹², —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-Z¹²,—(C₁-C₆)alkyl-S(O)—(C₂-C₆)alkenyl-Z¹²,—(C₂-C₆)alkyl-S(O)—(C₂-C₆)alkynyl-Z¹²,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹²,—(C₁-C₆)alkyl-SO₂—(C₂-C₆)alkenyl-Z¹²,—(C₂-C₆)alkyl-SO₂—(C₂-C₆)alkynyl-Z¹², —(C₂-C₆)alkyl-NR_(a)R_(b),—(C₂-C₆)alkylOC(O)—NR_(c)R_(d), —(C₂-C₆)alkyl-NR_(a)—C(O)—OR_(b),—(C₂-C₆)alkyl-NR_(a)—C(O)—NR_(a)R_(b), —(C₁-C₆)alkyl-SO₂(C₁-C₆)alkyl,—(C₁-C₆)alkyl-SO₂NR_(c)R_(d), —(C₁-C₆)alkyl-NR_(a)SO₂NR_(c)R_(d),—(C₁-C₆)alkyl-NR_(a)SO₂O(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-NR_(a)SO₂Oaryl,—(C₁-C₆)alkyl-NR_(a)—SO₂—(C₁-C₆)alkyl,—(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₁-C₆)alkyl,—(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkenyl,—(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkynyl,—(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, (C₁-C₆)alkyl-NR_(a)—SO₂-heteroaryl,—(C₁-C₆)alkyl-NR_(a)—SO₂-heterocycle, —O(C₁-C₆)alkyl-NR_(a)R_(b),—O(C₁-C₆)alkylOC(O)—NR_(c)R_(d), —O(C₁-C₆)alkyl-NR_(a)—C(O)—OR_(b),—O(C₁-C₆)alkyl-NR_(a)—C(O)—NR_(a)R_(b),—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₁-C₆)alkyl,—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkenyl,—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkynyl,—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, —O(C₁-C₆)alkyl-NR_(a)—SO₂-heteroaryl,—O(C₁-C₆)alkyl-NR_(a)—SO₂-heterocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂—NR_(a)R_(b),—O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, —O(C₁-C₆)alkyl-NR_(a)SO₂NR_(c)R_(d),—O(C₁-C₆)alkyl-NR_(a)SO₂O(C₃-C₇)carbocycle,—O(C₁-C₆)alkyl-NR_(a)SO₂Oaryl, —Oheteroaryl, —Oheterocycle,—Sheteroaryl, —Sheterocycle, —S(O)heteroaryl, —S(O)heterocycle,—SO₂heteroaryl or —SO₂heterocycle; wherein any (C₁-C₆)alkyl, aryl,(C₃-C₇)carbocycle, heteroaryl or heterocycle of R^(3b) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; andR^(3b′) is H, (C₁-C₆)alkyl or —O(C₁-C₆)alkyl; or R^(3b) and R^(3b′)together with the carbon to which they are attached form a heterocycleor (C₃-C₇)carbocycle which heterocycle or (C₃-C₇)carbocycle of R^(3b)and R^(3b′) together with the carbon to which they are attached isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

R^(4a) is selected from aryl, heterocycle and heteroaryl, wherein anyaryl, heterocycle and heteroaryl of R^(4a) is optionally substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) groups each independentlyselected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂,—NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂; wherein (C₁-C₆)alkyl isoptionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo;

R^(4b) is selected from;

a) (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl; wherein(C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl are each optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups;

b) (C₃-C₁₄)carbocycle; wherein (C₃-C₁₄)carbocycle is optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z groups; whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle;

c) Spiro-heterocycle or bridged-heterocycle; wherein spiro-heterocycleor bridged-heterocycle is optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z¹ groups; or wherein two Z¹ groups together with theatom or atoms to which they are attached optionally form a(C₃-C₇)carbocycle or heterocycle;

d) aryl, heteroaryl, spiro-, fused-, or bridged-heterocycle; whereinaryl, heteroaryl, or spiro-, fused-, or bridged-heterocycle are eachindependently substituted with one or more Z⁷ groups and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; or

R⁴ and R³ together with the atoms to which they are attached form amacroheterocycle or a macrocarbocycle wherein any macroheterocycle ormacrocarbocycle of R⁴ and R³ together with the atoms to which they areattached may be optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups; and R^(3b′) is H or (C₁-C₆)alkyl, —O(C₁-C₆)alkyl.

R^(5a) is selected from:

a) halo, nitro and cyano;

b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹; wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; wherein aryl,heterocycle and heteroaryl are each optionally substituted with one ormore (e.g. 1, 2 or 3) Z¹¹ groups;

c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰, and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰; whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; and each R¹⁰ is independently selected from R¹¹,—(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹;wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl,aryl, heterocycle and heteroaryl;

R^(5b) is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,(C₁-C₆)alkylS(O)—(C₁-C₆)alkyl-(C₃-C₆)carbocycle,—(C₁-C₆)alkylSO₂(C₃-C₇)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,—(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ or -halo(C₁-C₆)alkyl-Z³; wherein (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl or heteroaryl are each optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle wherein the(C₃-C₇)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl; wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups;

d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl,—X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle; wherein (C₁-C₆)alkyl or(C₁-C₆)haloalkyl are each substituted with one or more Z³ groups andoptionally substituted with one or more Z¹ groups; and wherein(C₂-C₆)alkenyl, (C₂-C₆)alkynyl and (C₃-C₇)carbocycle are eachindependently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁴groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle; wherein aryl heteroaryl are heterocycle are eachindependently substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁵groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl; where (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f);wherein each (C₁-C₆)alkyl is independently substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R^(6a) is selected from:

a) H, halo, (C₁-C₆)alkyl, and (C₁-C₆)haloalkyl

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle or heteroaryl;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹; wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰; whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; and

each R¹¹ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹,—SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰; wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl; and

wherein any aryl, heterocycle or heteroaryl of R^(6a) is optionallysubstituted with one or more (e.g. 1, 2 or 3) Z¹⁰ groups;

R^(6b) is selected from:

a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ or -halo(C₁-C₆)alkyl-Z³; wherein (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl or heteroaryl are optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a carbocycle or heterocycle wherein the carbocycle orheterocycle is optionally substituted with one or more Z¹ groups;

c) (C₁-C₆)alkyl; wherein (C₁-C₆)alkyl is substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z² groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl,—X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle; wherein (C₁-C₆)alkyl or(C₁-C₆)haloalkyl are each independently substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z³ groups and optionally substituted with one ormore Z¹ groups; and wherein (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and(C₃-C₇)carbocycle are each independently substituted with one or more Z⁴groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocyclewherein aryl heteroaryl and heterocycle are each independentlysubstituted with one or more Z⁵ groups and optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and(C₂-C₆)alkynyl; wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f);wherein each (C₁-C₆)alkyl is independently substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

R^(7a) is selected from:

a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl;

b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano,aryl, heterocycle and heteroaryl;

c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹; wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and

d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰; whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; and

each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹,—SO₂—R¹¹, —C(═O)—R¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹; wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl; and wherein any aryl, heterocycle or heteroaryl ofR^(1a) is optionally substituted with one or more (e.g. 1, 2 or 3) Z¹⁰groups;

R^(7b) is selected from:

a) —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³,—O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z³, —S(O)—(C₁-C₆)alkyl-Z¹³,—SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴,—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,—(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, (C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ or -halo(C₁-C₆)alkyl-Z³; wherein (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl or heteroaryl are each optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups;

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle wherein the(C₃-C₆)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl; wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups;

d) —X(C₁-C₆)alkyl, X(C₁-C₆)haloalkyl, X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyland —X(C₃-C₇)carbocycle; wherein (C₁-C₆)alkyl and (C₁-C₆)haloalkyl areeach substituted with one or more Z³ groups and optionally substitutedwith one or more Z¹ groups; and wherein (C₂-C₆)alkenyl, (C₂-C₆)alkynyland (C₃-C₇)carbocycle are each substituted with one or more (e.g. 1, 2,3, 4 or 5) Z⁴ groups and optionally substituted with one or more (e.g.1, 2, 3, 4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and—Xheterocycle; wherein aryl, heteroaryl and heterocycle are eachsubstituted with one or more Z⁵ groups and optionally substituted withone or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl; wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or moreZ⁶ groups and optionally substituted with one or more (e.g. 1, 2, 3, 4or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),—(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f);wherein each (C₁-C₆)alkyl is substituted with one or more (e.g. 1, 2, 3,4 or 5) Z⁶ groups and optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) Z¹ groups;

R^(8a) is selected from:

a) halo, nitro and cyano;

b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹,—(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹,—(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and—(C₁-C₆)alkyl-SO₂—R¹¹; wherein each R¹¹ is independently selected fromH, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,(C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; wherein aryl,heterocycle and heteroaryl are each optionally substituted with one ormore (e.g. 1, 2 or 3) Z¹¹ groups;

c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰,—(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰; whereineach R⁹ is independently selected from H, (C₁-C₆)alkyl and(C₃-C₇)cycloalkyl; and

each R¹¹ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹,—C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰; wherein each R¹¹ isindependently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycleand heteroaryl;

R^(8b) is selected from:

a) —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z³,—O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³,—SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴,—(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³,—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle,—(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl,-halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl,—(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl,—(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle,—(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl,—(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle,—(C₃-C₇)carbocycle-Z¹ or -halo(C₁-C₆)alkyl-Z³; wherein (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl or heteroaryl are each optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups:

b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle andbridged-bicyclic carbocycle; wherein spiro-bicyclic carbocycle,fused-bicyclic carbocycle or bridged-bicyclic carbocycle are optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; whereintwo Z¹ groups together with the atom or atoms to which they are attachedoptionally form a (C₃-C₇)carbocycle or heterocycle wherein the(C₃-C₇)carbocycle or heterocycle is optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

c) (C₁-C₆)alkyl; wherein (C₁-C₆)alkyl is substituted with one or more Z²groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups;

d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl,—X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle; wherein (C₁-C₆)alkyl and(C₁-C₆)haloalkyl are each independently substituted with one or more Z³groups and optionally substituted with one or more (e.g. 1, 2, 3, 4 or5) Z¹ groups; and wherein any (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and(C₃-C₇)carbocycle are each independently substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z⁴ groups and optionally substituted with one ormore (e.g. 1, 2, 3, 4 or 5) Z¹ groups;

e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocyclewherein any aryl heteroaryl and heterocycle are each independentlysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z⁵ groups andoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹groups;

f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and(C₂-C₆)alkynyl; wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle,(C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substitutedwith one or more (e.g. 1, 2, 3, 4 or 5) Z⁶ groups and optionallysubstituted with one or more (e.g. 1, 2, 3, 4 or 5) Z¹ groups; and

g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f),—(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f),C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f); whereineach (C₁-C₆)alkyl is independently substituted with one or more (e.g. 1,2, 3, 4 or 5) Z⁶ groups and optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) Z¹ groups;

or any of R^(5a) and R^(6a), R^(6a) and R^(7a), R^(7a) and R^(8a), R¹and R⁸ or R¹ and R² together with the atoms to which they are attachedform a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-memberedheterocycle; wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or7-membered heterocycle is optionally substituted with one or more (e.g.1, 2 or 3) substituents each independently selected from halo,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH,—O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and—N((C₁-C₆)alkyl)₂;

or any of R⁵ and R⁶, R⁶ and R⁷ or R⁷ and R⁸, together with the atoms towhich they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6or 7-membered heterocycle; wherein the 5 or 6-membered carbocycle or a4, 5, 6 or 7-membered heterocycle are each independently substitutedwith one or more (e.g. 1, 2 or 3) Z⁷ or Z⁸ groups; wherein when two Z⁷groups are on same atom the two Z⁷ groups together with the atom towhich they are attached optionally form a (C₃-C₇)carbocycle or 4, 5 or6-membered heterocycle;

or R¹ and R⁸ or R¹ and R² together with the atoms to which they areattached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-memberedheterocycle; wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or7-membered heterocycle are each independently substituted with one ormore (e.g. 1, 2 or 3) Z⁷ or Z⁸ groups; wherein when two Z⁷ groups are onsame atom the two Z⁷ groups together with the atom to which they areattached optionally form a (C₃-C₇)carbocycle or 4, 5 or 6-memberedheterocycle;

X is independently selected from O, —C(O)—, —C(O)O—, —S—, —S(O)—, —SO₂,—(C₁-C₆)alkylO—, —(C₁-C₆)alkylC(O)—, —(C₁-C₆)alkylC(O)O—,—(C₁-C₆)alkylS—, —(C₁-C₆)alkylS(O)—, —(C₁-C₆)alkylSO₂—;

each Z¹ is independently selected from halo, —NO₂, —OH, ═NOR_(a), —SH,—CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₁-C₆)haloalkyl,(C₃-C₇)carbocycle, —(C₃-C₇)halocarbocycle, -aryl, -heteroaryl,-heterocycle, —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl,—O(C₁-C₆)haloalkyl, —O(C₃-C₇)carbocycle, —O(C₃-C₇)halocarbocycle,—Oaryl, —Oheteroaryl, —Oheterocycle, —S(C₁-C₆)alkyl, —S(C₂-C₆)alkenyl,—S(C₂-C₆)alkynyl, —S(C₁-C₆)haloalkyl, —S(C₃-C₇)carbocycle,—S(C₃-C₇)halocarbocycle, —Saryl, —Sheteroaryl, —Sheterocycle,—S(O)(C₁-C₆)alkyl, —S(O)(C₂-C₆)alkenyl, —S(O)(C₂-C₆)alkynyl,—S(O)(C₁-C₆)haloalkyl, —S(O) (C₃-C₇)carbocycle,—S(O)(C₃-C₇)halocarbocycle, —SO₂(C₁-C₆)alkyl, —S(O)aryl,—S(O)carbocycle, —S(O)heteroaryl, —S(O)heterocycle, —SO₂(C₂-C₆)alkenyl,—SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(C₃-C₇)carbocycle,—SO₂(C₃-C₇)halocarbocycle, —SO₂aryl, —SO₂heteroaryl, —SO₂heterocycle,—SO₂NR_(c)R_(d), —NR_(c)R_(d), —NR_(a)C(O)R_(a), —NR_(a)C(O)ORa,—NR_(a)C(O)NR_(c)R_(d)—NR_(a)SO₂R_(b), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a), —C(O)R_(a),—C(O)OR_(b), —C(O)NR_(c)R_(d), and —OC(O)NR_(c)R_(d), wherein any(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C₃-C₇)halocarbocycle,(C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl orheterocycle of Z¹ is optionally substituted with one or more (e.g. 1, 2,3, 4 or 5) halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b), -heteroaryl,-heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl,—NHheterocycle, or —S(O)₂NR_(c)R_(d);

each Z² is independently selected from —NO₂, —CN, spiro-heterocycle,bridge-heterocycle, spiro-bicyclic carbocycle, bridged-bicycliccarbocycle, NR_(a)SO₂(C₃-C₇)carbocycle, —NR_(a)SO₂aryl,—NR_(a)SO₂heteroaryl, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z³ is independently selected from —NO₂, —CN, —OH, oxo, ═NOR_(a),thioxo, -aryl, -heterocycle, -heteroaryl, —(C₃-C₇)halocarbocycle,—O(C₁-C₆)alkyl, —O(C₃-C₇)carbocycle, —Ohalo(C₃-C₇)carbocycle, —Oaryl,—Oheterocycle, —Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle,—S(C₃-C₇)halocarbocycle, —Saryl, —Sheterocycle, —Sheteroaryl,—S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O) (C₃-C₇)halocarbocycle,—S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SOz₂aryl,—SO₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(b), —NR_(a)C(O)R_(b),—C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z⁴ is independently selected from halogen, —(C₁-C₆)alkyl,(C₃-C₇)carbocycle, -halo(C₁-C₆)alkyl, —NO₂, —CN, —OH, oxo, ═NOR_(a),thioxo, -aryl, -heterocycle, -heteroaryl, —(C₃-C₇)halocarbocycle,—O(C₁-C₆)alkyl, —O(C₃-C₇)carbocycle, —O(C₃-C₇)halocarbocycle, —Oaryl,—Oheterocycle, —Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle,—S(C₃-C₇)halocarbocycle, —Saryl, —Sheterocycle, —Sheteroaryl,—S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle,—S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SO₂aryl,—SO₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(b), —NR_(a)C(O)R_(a),—C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z⁵ is independently selected from —NO₂, —CN, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —NR_(a)SO₂(C₁-C₆)alkyl,—NR_(a)SO₂(C₂-C₆)alkenyl, —NR_(a)SO₂(C₂-C₆)alkynyl,—NR_(a)SO₂(C₃-C₇)carbocycle, —NR_(a)SO₂(C₃-C₇)halocarbocycle,—NR_(a)SO₂aryl, —NR_(a)SO₂heteraryl, —NR_(a)SO₂heteroaryl,—NR_(a)SO₂heterocycle, —NR_(a)C(O)alkyl, —NR_(a)C(O)alkenyl,—NR_(a)C(O)alkynyl, —NR_(a)C(O) (C₃-C₇)carbocycle,—NR_(a)C(O)(C₃-C₇)halocarbocycle, —NR_(a)C(O)aryl,—NR_(a)C(O)heteroaryl, —NR_(a)C(O)heterocycle, NR_(a)C(O)NR_(c)R_(d) andNR_(a)C(O)OR_(b);

each Z⁶ is independently selected from —NO₂, —CN, —NR_(a)R_(a),NR_(a)C(O)R_(b), —C(O)NR_(c)R_(d), —(C₃-C₇)halocarbocycle, -aryl,-heteroaryl, -heterocycle, —Oaryl, —Oheteroaryl, —Oheterocycle,—O(C₃-C₇)halocarbocycle, —O(C₁-C₆)alkyl, —O(C₃-C₇)carbocycle,—Ohalo(C₁-C₆)alkyl, —Saryl, —Sheteroaryl, —Sheterocycle,—S(C₃-C₇)halocarbocycle, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle,—S(C₁-C₆)haloalkyl, —S(O)aryl, —S(O)heteroaryl, —S(O)heterocycle,—S(O)(C₃-C₇)halocarbocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle,—S(O)halo(C₁-C₆)alkyl, —SO₂aryl, —SO₂heteroaryl, —SOz₂heterocycle,—SO₂(C₁-C₆)alkyl, —SO₂halo(C₁-C₆)alkyl, —SO₂(C₃-C₇)carbocycle,—SO₂(C₃-C₇)halocarbocycle, —SO₂NR_(c)R_(d),—NR_(a)SO₂(C₃-C₇)halocarbocycle, —NR_(a)SO₂aryl, —NR_(a)SO₂heteraryl,—NR_(a)SO₂heteroaryl, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl.

each Z⁷ is independently selected from —NO₂, ═NOR_(a), —CN,—(C₁-C₆)alkyl-Z¹², —(C₂-C₆)alkenyl-Z¹², —(C₂-C₆)alkenylOH,—(C₂-C₆)alkynyl-Z¹², —(C₂-C₆)alkynyl-OH, —(C₁-C₆)haloalkyl-Z¹²,—(C₁-C₆)haloalkylOH, —(C₃-C₇)carbocycle-Z¹², —(C₃-C₇)carbocycleOH,—(C₃-C₇)halocarbocycle, —(C₁-C₆)alkylNR_(c)R_(d),—(C₁-C₆)alkylNR_(a)C(O)R_(a), —(C₁-C₆)alkylNR_(a)SO₂R_(a), -aryl,-heteroaryl, -heterocycle, —O(C₁-C₆)alkyl-Z¹², —O(C₂-C₆)alkenyl,—O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl, —O(C₃-C₇)carbocycle,—O(C₃-C₇)halocarbocycle, —Oaryl, —O(C₁-C₆)alkylNR_(c)R_(d),—O(C₁-C₆)alkylNR_(a)C(O)R_(a), —O(C₁-C₆)alkylNR_(a)SO₂R_(a),—Oheteroaryl, —Oheterocycle, —S(C₁-C₆)alkyl-Z¹², —S(C₂-C₆)alkenyl,—S(C₂-C₆)alkynyl, —S(C₁-C₆)haloalkyl, —S(C₃-C₇)carbocycle,—S(C₃-C₇)halocarbocycle, —S(C₁-C₆)alkylNR_(c)R_(d),—S(C₁-C₆)alkylNR_(a)C(O)R_(a), —S(C₁-C₆)alkylNR_(a)SO₂R_(a), —Saryl,—Sheteroaryl, —Sheterocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₂-C₆)alkenyl,—S(O)(C₂-C₆)alkynyl, —S(O)(C₁-C₆)haloalkyl, —S(O)(C₃-C₇)carbocycle,—S(O)(C₃-C₇)halocarbocycle, —SO₂(C₁-C₆)alkyl,—S(O)(C₁-C₆)alkylNR_(c)R_(d), —S(O)(C₁-C₆)alkylNR_(a)C(O)R_(a),—S(O)(C₁-C₆)alkylNR_(a)SO₂R_(a), —S(O)aryl, —S(O)heteroaryl,—S(O)heterocycle, —SO₂(C₁-C₆)alkyl, —SO₂(C₂-C₆)alkenyl,—SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(C₃-C₇)carbocycle,—SO₂(C₃-C₇)halocarbocycle, —SO₂aryl, —SO₂heteroaryl, —SO₂heterocycle,—SO₂(C₁-C₆)alkylNR_(c)R_(d), —SO₂(C₁-C₆)alkylNR_(a)C(O)R_(a),—SO₂(C₁-C₆)alkylNR_(a)SO₂R_(a), —SO₂NR_(c)R_(d), —NR_(a)C(O)OR_(b),—NR_(a)C(O)NR_(c)R_(d)—NR_(a)SO₂R_(b), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a),—C(O)NR_(c)R_(d), and —OC(O)NR_(c)R_(d), wherein any (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle,(C₃-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z⁷ isoptionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) halogen,—OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b), -heteroaryl, -heterocycle,—Oheteroaryl, —Oheterocycle, —NHheteroaryl, —NHheterocycle, or—S(O)₂NR_(c)R_(d).

each Z⁸ is independently selected from —NO₂ or —CN;

each Z⁹ is independently selected from —(C₁-C₆)alkyl, —O(C₁-C₆)alkyl;

each Z¹⁰ is independently selected from

-   -   i) halo, oxo, thioxo, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl,        (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-(C₁-C₆)alkyl-, —OH,        —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —SH, —S(C₁-C₆)alkyl,        —SO(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and        —N((C₁-C₆)alkyl)₂;    -   ii) (C₁-C₆)alkyl optionally substituted with —OH,        —O—(C₁-C₆)haloalkyl, or —O—(C₁-C₆)alkyl; and    -   iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle        and heteroaryl is optionally substituted with halo, (C₁-C₆)alkyl        or COOH;

each Z¹¹ is independently selected from Z¹⁰, —C(═O)—NH₂,—C(═O)—NH(C₁-C₄)alkyl, —C(═O)—N((C₁-C₄)alkyl)₂, —C(═O)-aryl,—C(═O)-heterocycle and —C(═O)-heteroaryl;

each Z¹² is independently selected from —NO₂, ═NOR_(a), thioxo, -aryl,-heterocycle, -heteroaryl, —(C₃-C₇)halocarbocycle, —(C₃-C₇)carbocycle,—O(C₃-C₇)carbocycle, —Ohalo(C₃-C₇)carbocycle, —Oaryl, —Oheterocycle,—Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle,—Shalo(C₃-C₇)carbocycle, —Saryl, —Sheterocycle, —Sheteroaryl,—S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)halo(C₃-C₇)carbocycle,—S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SO₂aryl,—SOz₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(a), —NR_(a)C(O)R_(b),—C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl;

each Z¹³ is independently selected from —NO₂, —OH, ═NOR_(a), —SH, —CN,—(C₃-C₇)halocarbocycle, —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl,—O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl, —O(C₃-C₇)carbocycle,—O(C₃-C₇)halocarbocycle, —Oaryl, —Oheteroaryl, —Oheterocycle,—S(C₁-C₆)alkyl, —S(C₂-C₆)alkenyl, —S(C₂-C₆)alkynyl, —S(C₁-C₆)haloalkyl,—S(C₃-C₇)carbocycle, —S(C₃-C₇)halocarbocycle, —Saryl, —Sheteroaryl,—Sheterocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₂-C₆)alkenyl,—S(O)(C₂-C₆)alkynyl, —S(O)(C₁-C₆)haloalkyl, —S(O)(C₃-C₇)carbocycle,—S(O)(C₃-C₇)halocarbocycle, —S(O)aryl, —S(O)heteroaryl,—S(O)heterocycle, —SO₂(C₁-C₆)alkyl, —SO₂(C₂-C₆)alkenyl,—SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(C₃-C₇)carbocycle,—SO₂(C₃-C₇)halocarbocycle, —SO₂aryl, —SO₂heteroaryl, —SO₂heterocycle,—SO₂NR_(c)R_(d), —NR_(c)R_(d), —NR_(a)C(O)R_(a), —NR_(a)C(O)OR_(b),—NR_(a)C(O)NR_(c)R_(d)—NR_(a)SO₂R_(b), —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a), —C(O)R_(a),—C(O)OR_(b), —C(O)NR_(c)R_(d), and —OC(O)NRIRd; wherein any(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C₃-C₇)halocarbocycle,(C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl orheterocycle of Z¹³ is optionally substituted with one or more (e.g. 1,2, 3, 4 or 5) halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b),-heteroaryl, -heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl,—NHheterocycle, or —S(O)₂NR_(c)R_(d);

each Z¹⁴ is independently selected from —NO₂, ═NOR_(a), —CN,—(C₃-C₇)halocarbocycle, —O(C₃-C₇)halocarbocycle,—S(C₃-C₇)halocarbocycle, —S(O)(C₃-C₇)halocarbocycle,—SO₂(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d),—NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a); wherein any—(C₃-C₇)halocarbocycle of Z¹⁴ is optionally substituted with one or more(e.g. 1, 2, 3, 4 or 5) halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b),-heteroaryl, -heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl,—NHheterocycle, or —S(O)₂NR_(c)R_(d);

each R_(a) is independently H, (C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl,aryl(C₁-C₆)alkyl-, heteroaryl or heteroaryl(C₁-C₆)alkyl-; wherein any(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle,heterocycle, aryl, or heteroaryl of R_(a) is optionally substituted byhalogen, OH and cyano;

each R_(b) is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl,aryl(C₁-C₆)alkyl-, heteroaryl or heteroaryl(C₁-C₆)alkyl-; wherein any(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, (C₃-C₇)carbocycle,heterocycle, aryl, or heteroaryl of R_(b) is optionally substituted byhalogen, OH and cyano;

R_(c) and R_(d) are each independently selected from H, (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, aryl,aryl(C₁-C₆)alkyl-, heterocycle, heteroaryl or heteroaryl(C₁-C₆)alkyl-wherein any (C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,(C₃-C₇)carbocycle, heterocycle, aryl, or heteroaryl of R_(c) or R_(d) isoptionally substituted by halogen, OH and cyano; or R_(c) and R_(d)together with the nitrogen to which they are attached form aheterocycle; wherein any heterocycle of R_(c), and R_(d) together withthe nitrogen to which they are attached is optionally substituted byhalogen, OH or cyano;

each R_(e) is independently selected from —OR_(a), (C₁-C₆)alkyl or(C₃-C₇)carbocycle wherein (C₁-C₆)alkyl or (C₃-C₇)carbocycle issubstituted by one or more Z_(d) and optionally substituted with one ormore Z₁; —(C₂-C₆)haloalkyl, —(C₂-C₆)alkenyl, or —(C₂-C₆)alkynyl whereinany haloalkyl, alkenyl or alkynyl is optionally substituted with one ormore Z₁; aryl, heterocycle or heteroaryl wherein aryl, heterocycle orheteroaryl is substituted by one or more Z_(c);

each R_(f) is independently selected from —R_(g), —OR_(a),—(C₁-C₆)alkyl-Z⁶, —SO₂R_(g), —C(O)R_(g), C(O)OR_(g), or—C(O)NR_(e)R_(g); and

each R_(g) is independently selected from —OR_(a), (C₁-C₆)alkyl,(C₃-C₇)carbocycle (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl, heterocycle or heteroaryl wherein any (C₁-C₆)alkyl,(C₃-C₇)carbocycle —(C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,aryl, heterocycle or heteroaryl of R_(g) is optionally substituted withone or more Z₁ groups;

or a salt thereof.

In one embodiment, the compounds of formula I include:

and salts thereof.

In another embodiment, the compounds of formula I include:

and salts thereof.

In another embodiment, the compounds of formula I include:

wherein each R^(y) is independently H or (C₁-C₆)alkyl and salts thereof.

In another embodiment, the compounds of formula I include:

or a salt thereof.

In another embodiment, the compounds of formula I include:

and salts thereof.

In another embodiment, the compounds of formula I include:

and salts thereof.

In another embodiment the compounds of formula I include compounds151-180 as described in Example 149.

General Synthetic Procedures

Scheme 1 is provided as a further embodiment of the invention andillustrates a process that was used to prepare a compound of formula Iand which can be used to prepare other compounds of formula I. Schemes2-6 are also provided as further embodiments of the invention andillustrate processes that can be used to prepare compounds of formula I.

An aromatic or heteroaromatic halide or triflate (1A) can becrossed-coupled to a suitably protected alkyne (1B) such asethynyl(trimethyl)silane using a palladium catalyst and copper halidesalt such as, for example, copper(I) iodide, N,N-diisopropylethylamine,tetrakis(triphenylphosphine)palladium(0) and dimethylformamide orcopper(I) iodide, diethylamine, and bis(triphenylphosphine)palladium(II) dichloride. Deprotection of cross-coupled alkyne (1C)yields the corresponding terminal alkyne (1D) such as, for example,deprotection of a trimethylsilyl-protected alkyne with a fluoride sourcesuch as, for example, tetrabutylammonium fluoride. Metalation of aterminal alkyl (1D) such as, for example, deprotonation withn-butyllithium, yields the corresponding metal acetylide such as, forexample lithium acetylide, that undergoes nucleophilic addition to anappropriate electrophile (1E) to give the corresponding hydroxy alkyneaddition product 1F. A suitably substituted phenyl electrophile such asphenyl-2-propanone can be purchased or prepared by those skilled in theart through, for example, Friedel-Crafts alkylation of benzene withchloroacetone.

The hydroxyl alkyne 1F can undergo 6-endo-dig electrophilic cyclizationunder suitable reaction conditions such as, for example iodine andsodium bicarbonate to give the corresponding substituted naphthalenesuch as, for example the iodonaphthalene 1G. The substituted naphthalene1G, can undergo a cross-coupling reaction such as, for example Stillecross-coupling using a tin reagent such as tributyl(vinyl)tin and apalladium catalyst such as bis(triphenylphosphine) palladium(II)dichloride to give the corresponding cross-coupled naphthalene such as,for example, vinylnaphthalene 1H.

The vinylnaphthalene 1H can be dihydroxylated by methods known to thoseskilled in the art such as, for example Sharpless asymmetricdihydroxylation using, for example, commercially available AD-mix-α.

The resulting diol 11 can be protected at the primary hydroxyl bysuitable protecting groups such as, for example, pivalate ester usingpivaloyl chloride and pyridine to provide 1J. The secondary hydroxyl canbe converted to the corresponding ether 1K such as tert-butyl etherusing methods known to those skilled in the art such as, for example,tert-butyl acetate and perchloric acid. The protected primary hydroxylcan be deprotected by methods known to those skilled in the art such as,for example the deprotection of a pivalate protecting group under basicconditions, such as, for example sodium hydroxide, to give thecorresponding primary hydroxyl compound 1L. The primary hydroxyl can beoxidized to the corresponding carboxylic acid 1M by methods known tothose skilled in the art such as, for example, periodic acid andchromium trioxide.

Metalation of a suitably functionalized and protected terminal alkynesuch as, for example, deprotonation with n-butyllithium, can yield thecorresponding metal acetylide such as, for example lithium acetylide,that undergoes nucleophilic addition to an appropriate electrophile,such as, for example 1E, to give the corresponding hydroxy alkyneaddition product 2A. The hydroxyl alkyne 2A can undergo 6-endo-digelectrophilic cyclization under suitable reaction conditions such as,for example iodine and sodium bicarbonate to give the correspondingsubstituted naphthalene such as, for example iodonaphthalene 2B. Thesubstituted naphthalene 2B, can undergo a cross-coupling reaction suchas, for example Stille cross-coupling using a tin reagent such as, forexample, tributyl(vinyl)tin and a palladium catalyst such as, forexample, bis(triphenylphosphine)palladium(II) dichloride to give thecorresponding cross-coupled naphthalene such as, for example,vinylnaphthalene 2C. The alkenylnaphthalene 2C can be dihydroxylatedusing methods known to those skilled in the art such as, for exampleSharpless asymmetric dihydroxylation using, for example, commerciallyavailable AD-mix-α.

The resulting diol 2D can be protected at the primary hydroxyl by anorthogonal protecting groups, such as, for example, pivalate ester usingpivaloyl chloride and pyridine. The secondary hydroxyl of 2E can beconverted to the corresponding ether 2F, such as a tert-butyl etherusing methods known to those skilled in the art for example, usingtert-butyl acetate and perchloric acid. The naphthol protecting groupcan be differentially deprotected by methods known to those skilled inthe art and converted to a leaving group (e.g. triflate) known toundergo cross-coupling reactions. The corresponding activatednaphthalene 2G can undergo cross-coupling reactions such as but notlimited to Suzuki reactions with boronic acids or esters, Stillereactions with trialkylstannane reagents, and Buchwald-Hartwig reactionswith amines thus providing carbon linked and nitrogen linked R⁴ groupsof 2H. The protected primary hydroxyl can be deprotected by methodsknown to those skilled in the art such as, for example the deprotectionof a pivalate protecting group under basic conditions, such as, forexample sodium hydroxide, to give the corresponding primary hydroxyl.The primary hydroxyl can be oxidized to the corresponding carboxylicacid analog 21 by methods known to those skilled in the art such as, forexample, periodic acid and chromium trioxide.

The substituted hydroxyl naphthalene 2J can undergo halogenation usingan appropriate halogen source and catalyst such as, for exampleN-chlorosuccinimide and zirconium(IV) chloride to provide 2K. Thehydroxyl naphthalene 2K can be converted to a leaving group such as, forexample trifluoromethanesulfonate ester by treatment withtrifluoromethanesulfonic anhydride and base such as, for example,2,6-lutidine to provide 2L. Naphthalene 2L can undergo a selectivecross-coupling reaction such as, for example Stille cross-coupling usinga tin reagent such as tributyl(vinyl)tin and a palladium catalyst suchas bis(triphenylphosphine) palladium(II) dichloride to give thecorresponding cross-coupled naphthalene such as vinylnaphthalene 2M. Thealkenylnaphthalene can be dihydroxylated to provide 2N by methods knownto those skilled in the art such as, Sharpless asymmetricdihydroxylation using, for example, commercially available AD mix-α.

The resulting diol 2N can be protected at the primary hydroxyl bysuitable protecting groups such as pivalate ester using pivaloylchloride and pyridine to provide 2P. The secondary hydroxyl can beconverted to the corresponding ether such as tert-butyl ether usingmethods known to those skilled in the art such as, tert-butyl acetateand perchloric acid to provide 2Q. The halogenated naphthalene 2Q canundergo cross-coupling reaction such as Suzuki cross-coupling using aboronic acid and a palladium catalyst such as palladium(II) acetate withSPhos to give the corresponding cross-coupled naphthalene 2R. Theprotected primary hydroxyl can be deprotected by methods known to thoseskilled in the art such as the deprotection of a pivalate protectinggroup under basic conditions for example, using sodium hydroxide, togive the corresponding primary hydroxyl compound 2R. The primaryhydroxyl can be oxidized to the corresponding carboxylic acid 2S bymethods known to those skilled in the art such as, for example, periodicacid and chromium trioxide.

Electrophilic aromatic substitution with a suitably functionalized andprotected naphthol such as, for example 4A″, with an electrophile suchas, for example, ethyl glyoxylate under appropriate conditions such as,for example, titanium tetrachloride, can provide 4B″. The secondaryalcohol can be protected with a protecting group and the naphtholconverted to a leaving group (e.g. triflate) known to undergocross-coupling reactions to provide 4C″. The alcohol protecting groupcan be removed and the resulting alcohol oxidized to the ketone using anoxidant such as Dess-Martin Periodinane, for example, to provide 4E″.The ketone can be reduced stereoselectively using an asymmetricreduction method such as, for example Corey-Bakshi-Shibata Reduction toprovide 4F″.

The secondary hydroxyl can be converted to the corresponding ether suchas tert-butyl ether using methods known to those skilled in the art suchas, tert-butyl acetate and perchloric acid to provide 4G″. Thefunctionalized naphthalene 4G″ can undergo can undergo cross-couplingreactions such as but not limited to Suzuki reactions with boronic acidsor esters, Stille reactions with trialkylstannane reagents, andBuchwald-Hartwig reactions with amines thus providing carbon linked andnitrogen linked products using a palladium catalyst such aspalladium(II) acetate with SPhos to give the corresponding cross-couplednaphthalene 4H″. The protected ester can be deprotected by methods knownto those skilled in the art such as, for example the deprotection of aethyl ester protecting group under basic conditions, such as, forexample sodium hydroxide, to give the corresponding carboxylic acid 4I″.

It is known to those skilled in the art that the functionalizednaphthalenes (e.g. 4E″, 4G″, or 4H1″) that contain a halogen orpseudohalogen (e.g. triflate), can undergo cross-coupling reactions suchas but not limited to Suzuki reactions with boronic acids or esters,Stille reactions with trialkyltin reagents, Sonogashira reactions withalkynes, and Buchwald-Hartwig reactions with amines and carried forwardin a similar manner to provide 4″I.

The functionalized naphthalene 4C″ can undergo can undergocross-coupling reactions such as but not limited to Suzuki reactionswith boronic acids or esters, Stille reactions with trialkyltinreagents, Sonogashira reactions with alkynes, and Buchwald-Hartwigreactions with amines thus providing carbon linked and nitrogen linkedproducts using a palladium catalyst such as palladium tetrakis to givethe corresponding cross-coupled naphthalene 5A″. The alcohol protectinggroup can be removed and the resulting alcohol oxidized to the ketoneusing an oxidant such as Dess-Martin Periodinane, for example, toprovide 5B″. The ketone can be reduced stereoselectively using anasymmetric reduction method such as, for example Corey-Bakshi-ShibataReduction to provide 5C″. The secondary hydroxyl can be converted to thecorresponding ether such as tert-butyl ether using methods known tothose skilled in the art such as, tert-butyl acetate and perchloric acidto provide 5D″. The protected ester can be deprotected by methods knownto those skilled in the art such as, for example the deprotection of aethyl ester protecting group under basic conditions, such as, forexample sodium hydroxide, to give the corresponding carboxylic acid 5E″.

It is known to those skilled in the art that the functionalizednaphthalenes (e.g. 5A″ or 5D″) that contain a halogen or pseudohalogen(e.g. triflate), can undergo cross-coupling reactions such as but notlimited to Suzuki reactions with boronic acids or esters, Stillereactions with trialkyltin reagents, Sonogashira reactions with alkynes,and Buchwald-Hartwig reactions with amines and carried forward in asimilar manner to provide 5E″.

It is known to those skilled in the art that 6A″ can undergo TheHorner-Wadsworth-Emmons with stabilized phosphonate carbanions such as,for example (diethoxyphosphoryl)acetic acid ethyl ester and sodiumhydride to provide 6B″. The olefin can be reduced by hydrogenation withpalladium on carbon, for example, to provide 6C″. The protected estercan be deprotected by methods known to those skilled in the art such as,for example the deprotection of a ethyl ester protecting group underbasic conditions, such as, for example lithium hydroxide, to give thecorresponding carboxylic acid that can be converted to the correspondingacid chloride using oxalyl chloride to give 6D″. Friedel Crafts reactioncatalyzed by a Lewis acid such as, for example, aluminum trichlorideprovides tetralone 6E″. Condensation of 6E″ with, for example, ethylglyoxylate under acid catalysis provides 6F″ which can be brominatedunder radical conditions such as, for example, N-bromosuccinimide andAIBN, and converted to 6H″ using an alkoxide such as that derived fromreaction of 4-methoxybenzyl alcohol and LHMDS, for example.

The naphthol 6H″ can be converted to a leaving group (e.g. triflate)known to undergo cross-coupling reactions by methods known to thoseskilled in the art. Compound 6I″ can undergo cross-coupling reactionssuch as but not limited to Suzuki reactions with boronic acids oresters, Stille reactions with trialkyltin reagents, Sonogashirareactions with alkynes, and Buchwald-Hartwig reactions with amines thusproviding carbon linked and nitrogen linked products using a palladiumcatalyst such as palladium tetrakis to give the correspondingcross-coupled naphthalene 6J″.

The alcohol protecting group can be removed by methods known to thoseskilled in the art and the resulting hydroxyl can be converted to thecorresponding ether such as tert-butyl ether using methods known tothose skilled in the art such as, tert-butyl acetate and perchloric acidto provide 6K″. The protected ester can be deprotected by methods knownto those skilled in the art such as, for example the deprotection of aethyl ester protecting group under basic conditions, such as, forexample sodium hydroxide, to give the corresponding carboxylic acid 6L″.

Prodrugs

In one embodiment, the invention provides for a prodrug of a compound ofthe invention. The term “prodrug” as used herein refers to any compoundthat when administered to a biological system generates a compound ofthe invention that inhibits the replication of HIV (“the activeinhibitory compound”). The compound may be formed from the prodrug as aresult of: (i) spontaneous chemical reaction(s), (ii) enzyme catalyzedchemical reaction(s), (iii) photolysis, and/or (iv) metabolic chemicalreaction(s).

“Prodrug moiety” refers to a labile functional group which separatesfrom the active inhibitory compound during metabolism, systemically,inside a cell, by hydrolysis, enzymatic cleavage, or by some otherprocess (Bundgaard, Hans, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development (1991), P. Krogsgaard-Larsen andH. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymeswhich are capable of an enzymatic activation mechanism with the prodrugcompounds of the invention include, but are not limited to, amidases,esterases, microbial enzymes, phospholipases, cholinesterases, andphosphases. Prodrug moieties can serve to enhance solubility, absorptionand lipophilicity to optimize drug delivery, bioavailability andefficacy. A prodrug moiety may include an active metabolite or drugitself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂OC(═O)R⁹⁹ and acyloxymethyl carbonates—CH₂OC(═O)OR⁹⁹ where R⁹⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.Subsequently, the acyloxyalkyl ester was used to deliver phosphonicacids across cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂C(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC)—CH₂C(═O)OC(CH₃)₃.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to aphosphate have also been described (Khamnei and Torrence, (1996) J. Med.Chem. 39:4109-4115). Benzyl esters are reported to generate parentphosphonic acids. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g., esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatephosphoric acid and a quinone methide intermediate. Examples of thisclass of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc.Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria etal. (1996) J. Med. Chem. 39: 4958).

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers and optionally other therapeuticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation andphysiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulfoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween®60, Span®80, cetostearyl alcohol, benzylalcohol, myristyl alcohol, glyceryl mono-stearate and sodium laurylsulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents.

Pharmaceutical formulations containing the active ingredient may be inany form suitable for the intended method of administration. When usedfor oral use for example, tablets, troches, lozenges, aqueous or oilsuspensions, dispersible powders or granules, emulsions, hard or softcapsules, syrups or elixirs may be prepared. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable.

These excipients may be, for example, inert diluents, such as calcium orsodium carbonate, lactose, lactose monohydrate, croscarmellose sodium,povidone, calcium or sodium phosphate; granulating and disintegratingagents, such as maize starch, or alginic acid; binding agents, such ascellulose, microcrystalline cellulose, starch, gelatin or acacia; andlubricating agents, such as magnesium stearate, stearic acid or talc.Tablets may be uncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyl oxidewith a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provides compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

The antiviral properties of a compound of the invention may bedetermined using Test A described below.

Test A: Antiviral Assays in MT4 Cells

For the antiviral assay utilizing MT-4 cells, 0.4 μL of 189X testconcentration of 3-fold serially diluted compound in DMSO was added to40 μL of cell growth medium (RPMI 1640, 10% FBS, 1%penicillin/Streptomycin, 1% L-Glutamine, 1% HEPES) in each well of384-well assay plates (10 concentrations) in quadruplicate.

1 mL aliquots of 2×10e6 MT-4 cells are pre-infected for 1 and 3 hrsrespectively, @37° C. with 25 μL (MT4) or of either cell growth medium(mock-infected) or a fresh 1:250 dilution of an HIV-IIIb concentratedABI stock (0.004 m.o.i. for MT4 cells). Infected and uninfected cellsare diluted in cell growth medium and 35 uL of 2000 (for MT4) cells isadded to each well of the assay plates.

Assay plates were then incubated in a 37° C. incubator. After 5 days ofincubation, 25 μl of 2× concentrated CellTiter-Glo™ Reagent (catalog#G7573, Promega Biosciences, Inc., Madison, Wis.) was added to each wellof the assay plate. Cell lysis was carried out by incubating at roomtemperature for 2-3 min and then chemiluminescence was read using theEnvision reader (PerkinElmer).

Compounds of the present invention demonstrate antiviral activity inthis assay (Test A) as depicted in the table below.

Compound Number EC50 (μM) 3K 0.056 4K 0.301 4L 22 5K 4.6 6D 0.014 7D 1.77E 20 8 0.025 9 1.3 10 36 11 8.9 12 0.11 13 0.010 14 0.011 15 0.015 167.0 17 7.7 19 5.4 20 0.093 22 0.54 23 0.024 24 29 25 26 26 0.84 27 3.528 0.40 29A 0.13 29B 0.50 30 0.044 31 0.11 32 0.086 33 0.12 34 0.35 371.2 38 3.4 39 0.70 40 0.21 41 0.40 42 0.11 43 0.022 44 0.12 45 1.8 461.4 47 0.11 48 0.21 49 0.65 53 0.12 54 0.055 55 0.054 56 0.21 57 0.08258 0.042 59 0.16 60 0.032 61 0.264 62 0.136 63 0.099 64 0.052 65 0.19 660.29 67 0.29 68A 0.014 68B 0.005 69 0.38 70 8.8 71 35 72 2.0 73 0.13 741.2 75 0.98 76 0.93 77 8.9 78 0.30 79 0.089 80 0.051 81 0.15 82 0.058 830.078 84 0.014 85 0.018 86 0.98 87 0.072 88 0.024 89 0.28 90 31 91 0.2592 7.1 93 0.086 94 12 95 0.38 96 0.088 97 0.30 98 0.010 99 0.107 1000.023 101 0.041 102 0.037 103 0.026 104 0.036 105 0.043 106A 0.086 106B0.091 107 0.092 108 0.028 109 29 110 0.067 111 1.1 112 0.009 113A 0.91113B 0.46 114 1.9 115 0.037 116 0.016 117 0.011 118 0.036 119 0.011 1200.032 121 0.014 122 0.036 123 0.024 124 0.15 126 0.833 127 0.087 128 5.3129 0.17 131 0.062 132 0.118 133 0.123 134 0.15 135 0.045 136 0.34 1370.13 138 0.040 139 0.010 140 1.6 143 0.056 144 1.3 145 0.050 146 10 1471.1 149 0.20 150A 29.150 150B 0.26 151 0.85 152 5.8 153 11 154 29 155 29156 7.3 157 10 158 35 159 1.3 160 36 161 4.7 162 1.4 163 16 164 25 16553 166 16 167 29 168 45 169 18 170 29 171 36 172 50 173 3.2 174 3.2 17520 176 12 177 37 178 34 179 18.7 180 29 181 0.005 183 0.351 185 0.024186A 1.694 186B 0.024

In certain embodiments, the compounds demonstrate an EC50 of <50 μM. Incertain embodiments, the compounds demonstrate an EC50 of <30 μM. Incertain embodiments, the compounds demonstrate an EC50 of <10 μM. Incertain embodiments, the compounds demonstrate an EC50 of <1 μM.

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present invention.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

The invention will now be illustrated by the following non-limitingExamples. The Examples provided herein describe the synthesis ofcompounds of the invention (i.e. compounds of Formula I) as well asintermediates used to prepare compounds of the invention.

Example 1(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (3K)

A stock solution of periodic acid/chromium trioxide was preparedaccording to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol)and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H₂O)to a volume of 114 mL. This stock solution (0.80 mL) was added to asolution of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethanol(3J) (51.7 mg, 0.14 mmol) in wet acetonitrile (2.0 mL), 0.75% H₂O) at 0°C. The reaction mixture was stirred for 30 minutes at 0° C. and quenchedwith 1.5 M K₂HPO₄ solution. Ethyl acetate was added and organic layerseparated and washed with 1:1 brine/H₂O (2×), then saturatedNaHSO₃/brine. The organic layer was dried (MgSO₄), filtered andconcentrated and purified by reverse phase HPLC (Gemini, 50 to 95%ACN/H₂O+0.1% TFA) and the product lyophilized to give 3K as a whitepowder (27.8 mg). ¹H-NMR: 300 MHz, (CDCl₃) δ 7.73 (d, J=7.8 Hz, 1H),7.64 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.50-7.38 (m, 3H), 7.28-7.22 (m,3H), 5.25 (s, 1H), 2.54 (s, 3H), 0.98 (s, 9H). LCMS-ESI⁻ (m/z): [M−H]⁻calcd for C₂₃H₂₂ClO₃: 381.88. Found: 380.9, 382.9.

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethanol(3J)

Preparation of 1-phenylpropan-2-one (3B): A stock solution of periodicacid/chromium trioxide was prepared according to WO 99/52850 bydissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23mg, 1.2 mol %) in wet acetonitrile (0.75% H₂O) to a volume of 114 mL.This stock solution (104.5 mL) was added to a solution of1-phenylpropan-2-ol (3A) (5.0 g, 36.71 mmol) in wet acetonitrile (150mL, 0.75% H₂O) at 0° C. over 1 h, maintaining internal temperature below5° C. The reaction was quenched with K₂HPO₄ (11.5 g, 50.5 mmol) in H₂O(60 mL). Dichloromethane was added and organic layer separated andwashed with brine/H₂O (2×100 mL), followed by saturated NaHSO₃/brine.The organic layer was dried (MgSO₄), filtered and concentrated to give3B as a yellow oil (5.1 g). ¹H-NMR: 300 MHz, (CDCl₃) δ 7.35-7.10 (m,5H), 3.65 (s, 2H), 2.11 (s, 3H).

Preparation of 4-(4-chlorophenyl)-2-methyl-1-phenylbut-3-yn-2-ol (3D):To a solution of 1-chloro-4-ethynylbenzene (3C) (1.75 mL, 12.81 mmol) inTHF (40 mL) at 0° C. was added n-butyllithium (2.5 M in hexanes, 5.13mL, 12.81 mmol) and stirred for 1 h. A solution of 1-phenylpropan-2-one(3B) (1.38 g, 10.25 mmol) in THF (5 mL) was added and the reactionmixture was warmed to room temperature overnight. The reaction mixturewas quenched with saturated NH₄Cl solution and extracted with diethylether (2×). The combined organic layer was dried (MgSO₄), filtered,concentrated and purified by flash column chromatography (silica gel, 0to 10% ethyl acetate/hexanes) to give 3D as a yellow oil (2.29 g).¹H-NMR: 300 MHz, (CDCl₃) δ 7.35-7.20 (m, 9H), 3.0 (AB quart, J=13.2, 9.9Hz, 2H), 1.59 (s, 3H).

Preparation of 1-(4-chlorophenyl)-2-iodo-3-methylnaphthalene (3E): To asolution of 4-(4-chlorophenyl)-2-methyl-1-phenylbut-3-yn-2-ol (3D) (1.77g, 6.53 mmol) in acetonitrile (50 mL) was added sodium bicarbonate(1.097 g, 13.06 mmol), followed by iodine (4.974 g, 19.60 mmol). Thereaction mixture was stirred for 1.5 h, then diluted with diethyl ether.The organic layer was washed with 1 M sodium thiosulfate solution (50mL). The aqueous layer was back-extracted with diethyl ether and thecombined organic layer was dried (MgSO₄), filtered, concentrated,adsorbed onto silica gel and purified by flash column chromatography(silica gel, hexanes) to give 3E as an off-white solid (1.8733 g).¹H-NMR: 300 MHz, (CDCl₃) δ 7.74 (d, J=6.6 Hz, 1H), 7.73 (s, 1H),7.48-7.40 (m, 3H), 7.24-7.20 (m, 2H), 7.13 (d, J=8.1 Hz, 2H), 2.64 (s,3H).

Preparation of 1-(4-chlorophenyl)-3-methyl-2-vinylnaphthalene (3F): Asolution of 1-(4-chlorophenyl)-2-iodo-3-methylnaphthalene (3E) (1.50 g,3.98 mmol), tributyl(vinyl)tin (1.28 mL, 4.37 mmol) and PdCl₂(PPh₃)₂(0.279 g, 0.398 mmol) in DMF (20 mL) was stirred at 90° C. under argonovernight. The reaction mixture was cooled, diluted with ethyl acetateand washed with 5% LiCl solution (2×), brine and dried (MgSO₄). Themixture was filtered, concentrated and purified by flash columnchromatography (silica gel, hexanes) to give 3F as a white solid (0.9894g). ¹H-NMR: 300 MHz, (CDCl₃) δ 7.74 (d, J=7.8 Hz, 1H), 7.66 (s, 1H),7.40-7.13 (m, 5H), 7.15 (d, J=8.1 Hz, 2H), 6.50 (dd, J=18, 11.7 Hz, 1H),5.27 (d, J=11.7 Hz, 1H), 5.03 (d, J=18 Hz, 1H), 2.50 (s, 3H).

Preparation of(S)-1-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethane-1,2-diol (3G):A biphasic mixture of AD-mix-α (4.928 g) in tert-butanol (17.5 mL)/H₂O(17.5 mL) was cooled to 0° C. and1-(4-chlorophenyl)-3-methyl-2-vinyl-naphthalene (3F) (0.980 g, 3.52mmol) was added. The reaction mixture was stirred for 6 h at 0° C., thenstored at −20° C. overnight. The reaction was resumed for 10 h at 0° C.,then stored at −20° C. overnight. The reaction was resumed for 8 h at 0°C. until complete. Sodium sulfite (5.3 g) was added at 0° C., thenwarmed to room temperature and stirred for 30 min to give a whitemixture. The mixture was diluted with dichloromethane and H₂O. Themixture was extracted with dichloromethane (3×) and the combined organiclayer was dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) togive 3G as a white solid (0.9813 g). ¹H-NMR: 300 MHz, (CDCl₃) δ 7.72 (d,J=8.1 Hz, 1H), 7.65 (s, 1H), 7.50-7.303 (m, 3H), 7.26-7.07 (m, 4H), 4.92(dd, J=9.9, 3.6 Hz, 1H), 3.94 (dd, J=10.2, 10.2 Hz, 1H), 3.57 (dd,J=11.1, 3.6 Hz, 1H), 2.69 (s, 3H).

Preparation of(S)-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyethylpivalate (3H): To a solution of(S)-1-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethane-1,2-diol (3G)(0.981 g, 3.14 mmol) in pyridine (5.0 mL)/DCM (15.0 mL) was addedpivaloyl chloride (0.463 mL, 3.77 mmol). The reaction mixture wasstirred for 5 h at room temperature and diluted with ethyl acetate. Theorganic layer was washed with 1 N HCl, saturated sodium bicarbonatesolution, dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 30% ethyl acetate/hexanes) togive 3H as a white solid (1.296 g). ¹H-NMR: 300 MHz, (CDCl₃): δ: 7.72(d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.46-7.37 (m, 3H), 7.26-7.10 (m, 4H),4.99 (dd, J=8.7, 3.0 Hz, 1H), 4.45 (dd, J=11.7, 9.7 Hz, 1H), 4.13 (dd,J=11.7, 3.3 Hz, 1H), 2.72 (s, 3H), 1.11 (s, 9H).

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethanol(3J): A solution of(S)-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyethylpivalate (3H) (0.4582 g, 1.15 mmol) and perchloric acid, (70%, 0.138 mL,2.3 mmol) in tert-butyl acetate (10 mL) was stirred at room temperaturefor 3 h. The reaction mixture was quenched with solid sodium bicarbonate(0.5 g) for 1 h. Saturated sodium bicarbonate solution was added andextracted with ethyl acetate (3×). The combined organic layer was dried(MgSO₄), filtered and concentrated to give(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethylpivalate (3I) that was used in next step without further purification.(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)ethylpivalate (31) from above reaction was dissolved in MeOH (1 mL) and THF(7 mL). Sodium hydroxide (2 M, 0.75 mL, 1.5 mmol) was added and thereaction mixture was stirred at room temperature overnight. Additionalsodium hydroxide (2 M, 0.75 mL, 1.5 mmol) was added and reaction mixturewas stirred for an additional 24 hours. The reaction mixture was thendiluted with ethyl acetate and washed with brine. The aqueous layer wasback-extracted with ethyl acetate and combined organic layer was dried(MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 3Jas a white solid (0.1889 g). ¹H-NMR: 300 MHz, (CDCl₃) δ 7.72 (d, J=8.1Hz, 1H), 7.63 (s, 1H), 7.46-7.05 (m, 7H), 4.60 (dd, J=10.5, 4.5 Hz, 1H),3.77 (dd, J=11.4, 4.2 Hz, 1H), 3.46 (dd, J=11.4, 4.2 Hz, 1H), 2.71 (s,3H), 1.00 (s, 9H).

Example 2(S)-2-tert-butoxy-2-((R)-3-methyl-1-(quinolin-8-yl)naphthalen-2-yl)aceticacid (4K) and(S)-2-tert-butoxy-2-((S)-3-methyl-1-(quinolin-8-yl)naphthalen-2-yl)aceticacid (4L)

(S)-2-tert-butoxy-2-((R)-3-methyl-1-(quinolin-8-yl)naphthalen-2-yl)ethylpivalate (4I) (22 mg, 0.0468 mmol) was dissolved in THF (1.0 mL) andMeOH (0.1 mL) and 2.0 M NaOH (94 μL) was added. The reaction mixture wasstirred for 24 h and 2.0 M NaOH (94 μL) was added. After stirring for 60h at room temperature, the reaction was heated at 55° C. for 1 h withlittle change in conversion. The reaction mixture was diluted with ethylacetate and washed with brine, dried (MgSO₄), filtered, concentrated andused in next step without further purification. The residue from abovewas dissolved in wet acetonitrile (0.75% H₂O), and H₅IO₆/CrO₃ stocksolution (0.439 M, 0.266 mL) was added at 0° C. The reaction mixture wasstirred for 30 minutes and additional H₅IO₆/CrO₃ stock solution (0.439M, 0.266 mL) was added. After stirring for 30 minutes, the reactionmixture was quenched with saturated NaHCO₃ solution and diluted withethyl acetate. The organic layer was washed with H₂O/brine, dried(MgSO₄), filtered, concentrated and purified by reverse phase HPLC(Gemini, 5 to 100% acetonitrile/H₂O+0.1% TFA) to give 4K as a film (12.1mg, 50%). ¹H-NMR: 400 MHz, (CD₃OD) δ 9.35 (dd, J=8.4, 1.6 Hz, 1H), 8.86(dd, J=5.6, 1.2 Hz, 1H), 8.51 (dd, J=8.4, 1.2 Hz, 1H), 8.13-8.07 (m,2H), 8.01 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.52-7.45 (m, 1H), 7.28-7.24(m, 1H), 6.83 (d, J=8.4 Hz, 1H), 5.23 (s, 1H), 2.80 (s, 3H), 0.84 (s,9H). ¹⁹F-NMR: 376 MHz, (CD₃OD) δ: −77.87. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₂₆H₂₆NO₃: 400.5. Found: 400.1.

Compound 4L (1.8 mg, 32%) was prepared following the procedure used toprepare compound 4K except that compound 4J was used instead of compound4I. ¹H-NMR: 400 MHz, (CD₃OD) δ 9.23 (dd, J=8.4, 1.6 Hz, 1H), 8.75 (dd,J=5.2, 1.6 Hz, 1H), 8.48 (dd, J=8.8, 1.6 Hz, 1H), 8.31 (dd, J=7.2, 1.2Hz, 1H), 8.13 (dd, J=7.6, 7.2 Hz, 1H), 7.99 (dd, J=8.4, 5.2 Hz, 1H),7.96 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.5-7.45 (m, 1H), 7.25-7.21 (m,1H), 6.83 (d, J=8.8 Hz, 1H), 5.16 (s, 1H), 2.75 (s, 3H), 0.83 (s, 9H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₆H₂₆NO₃: 400.5. Found: 400.1.

Preparation of(S)-2-tert-butoxy-2-((R)-3-methyl-1-(quinolin-8-yl)naphthalen-2-yl)ethylpivalate (4I) and(S)-2-tert-butoxy-2-((S)-3-methyl-1-(quinolin-8-yl)naphthalen-2-yl)ethylpivalate (4J):

Preparation of 1-chloro-3-methylnaphthalen-2-ol (4B): To a solution ofN-chlorosuccinimide (8.02 g, 60.05 mmol) in dichloromethane (475 mL) at−78° C. was added zirconium(IV)chloride (2.80 g, 12.01 mmol), followedby 3-methyl-naphthalen-2-ol (4A) (9.5 g, 60.05 mmol) under Ar. Thereaction mixture was stirred at −78° C. for minutes, the cooling bathwas removed and the reaction was stirred at room temperature for 5 h.The reaction was quenched with saturated sodium bicarbonate solution andstirred for 5 minutes. The mixture was diluted with H₂O, extracted withdichloromethane (3×) and the combined organic layer was dried (MgSO₄),filtered, concentrated and purified by flash column chromatography(silica gel, 0 to 10% ethyl acetate/hexanes) to give 4B as a white solid(9.05 g, 78%).

Preparation of 1-chloro-3-methylnaphthalen-2-yltrifluoromethanesulfonate (4C): To a solution of1-chloro-3-methylnaphthalen-2-ol (4B) (9.05 g, 46.98 mmol) indichloromethane (235 mL) at −78° C. was added trifluoromethanesulfonicanhydride (11.9 mL, 70.47 mmol), followed by 2,6-lutidine (8.2 mL, 70.47mmol). The reaction mixture was stirred for 3 h to give a yellowsolution, which was diluted with dichloromethane and washed withH₂O/brine. The organic layer was dried (MgSO₄), filtered, concentratedand purified by flash column chromatography (silica gel, 0 to 10% ethylacetate/hexanes) to give 4C as a white solid (14.75 g, 97%).

Preparation of 1-chloro-3-methyl-2-vinylnaphthalene (4D): To a solutionof 1-chloro-3-methylnaphthalen-2-yl trifluoromethanesulfonate (4C)(14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59 mL, 49.97 mmol) andlithium chloride (5.78 g, 136.29 mmol) was addedbis(triphenylphosphine)palladium(II) dichloride under Ar. The reactionmixture was heated at 50° C. for 20 h, then heated at 90° C. for 8 h.The reaction mixture was than cooled to room temperature, diluted withethyl acetate, washed with 5% lithium chloride solution (3×), brine anddried (MgSO₄), filtered and then concentrated and purified by flashcolumn chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) togive 4D contaminated by organotin. The residue was dissolved indichloromethane and stirred with 10% KF solution overnight. Theresulting white mixture was filtered through a pad of Celite andextracted with dichloromethane (2×). The organic layer was concentratedand purified by flash column chromatography (silica gel, 0 to 10% ethylacetate/hexanes) to give 4D as a pale yellow oil (10.1 g).

Preparation of (S)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol(4E): A biphasic mixture of AD-mix-α (6.907 g) in tert-butanol (24.5mL)/H₂O (24.5 mL) was cooled to 0° C. and1-chloro-3-methyl-2-vinylnaphthalene (4D) (1.00 g, 4.93 mmol) was added.The reaction mixture was stirred for 8 h at 0° C. Sodium sulfite (7.4 g)was added at 0° C. and the reaction was stirred for 40 minutes to give awhite mixture. The mixture was diluted with dichloromethane and H₂O. Themixture was extracted with dichloromethane (3×) and the combined organiclayer was dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) togive 4E as a white solid (0.920 g).

Preparation of (S)-2-(1-chloro-3-methylnaphthalen-2-yl)-2-hydroxyethylpivalate (4F): To a solution of(S)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (4E) (0.920 g,3.89 mmol) in pyridine (5.0 mL)/dichloromethane (15.0 mL) was addedpivaloyl chloride (0.574 mL, 4.67 mmol). The reaction mixture wasstirred for 18 h at room temperature. The reaction was incomplete andadditional pivaloyl chloride (0.574 mL, 4.67 mmol) was added. Afterstirring for 1 h, the reaction mixture was quenched with 1 N HCl anddiluted with ethyl acetate. The organic layer was washed with 1 N HCl,saturated sodium bicarbonate solution, dried (MgSO₄), filtered,concentrated and purified by flash column chromatography (silica gel, 0to 30% ethyl acetate/hexanes) to give 4F as a colorless oil (1.139 g).LCMS-ESI⁺ (m/z): [M—O]⁺ calcd for C₁₈H₂₁ClO₂: 304.80. Found: 303.0,305.0.

Preparation of(S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)ethyl pivalate(4G): A solution of(S)-2-(1-chloro-3-methylnaphthalen-2-yl)-2-hydroxyethyl pivalate (4F)(1.13 g, 3.52 mmol) and perchloric acid, (70%, 0.605 mL, 7.04 mmol) intert-butyl acetate (35 mL) was stirred at room temperature for 1.5 h.The reaction mixture was quenched with solid sodium bicarbonate (1.5 g)for 1 h. Saturated sodium bicarbonate solution was added and thereaction was extracted with ethyl acetate (3×). The combined organiclayer was dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) togive 4G as a colorless oil (1.1889 g, 90%).

Preparation of(S)-2-tert-butoxy-2-((R)-3-methyl-1-(quinolin-8-yl)naphthalen-2-yl)ethylpivalate (41) and(S)-2-tert-butoxy-2-((S)-3-methyl-1-(quinolin-8-yl)naphthalen-2-yl)ethylpivalate (4J): To a microwave vial was added(S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)ethyl pivalate(4G) (0.100 g, 0.265 mmol), 8-quinoline boronic acid (4H) (0.069 g,0.398 mmol), palladium(II) acetate (0.003 g, 0.013 mmol), SPhos (0.011g, 0.0265 mmol) and potassium phosphate (0.169 g, 0.795 mmol). The vialwas evacuated and backfilled with argon (3×). Anhydrous THF (0.53 mL)and H₂O (53 μL) were added and mixture stirred at room temperature for 2h and then heated at 50° C. for 2 h. The reaction was charged withPdCl₂(CH₃CN)₂ (10 mg) and SPhos (20 mg) and heated overnight at 100° C.The reaction mixture was diluted with ethyl acetate, washed with brine,dried (MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give theseparated atropisomers; atropisomer 41 (22.0 mg) LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₁H₃₆NO₃: 470.62. Found: 470.1; and atropisomer 4J (5.2 mg)LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₁H₃₆NO₃: 470.62; Found: 470.1.

Example 3(S)-2-tert-Butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (5K)

(S)-2-tert-Butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (5K) was prepared in a similar manner as compound 3K of Example 1except that compound 5J was used instead of compound 3J. ¹H-NMR: 300MHz, (CD₃OD) δ 8.54 (d, 1H), 8.08 (d, 1H), 7.86 (m, 2H), 7.57 (m, 1H),7.40 (m, 2H), 7.20 (m, 1H), 6.88 (m, 1H), 5.21 (s, 1H), 4.64 (dd, 2H),3.58 (dd, 2H), 2.66 (s, 3H), 0.84 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₂₈H₂₈NO₄: 442.2; Found: 442.1.

Preparation of(S)-2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethanol(5J)

Preparation of 1-bromo-3-methylnaphthalen-2-ol (5B):3-Methylnaphthalen-2-ol (4A) (2.09 g, 13.2 mmol) was taken in aceticacid (50 mL) and bromine (2.11 g) was added to it. The mixture wasstirred at room temperature for 20 minutes, concentrated and purified byflash chromatography (silica gel, ethyl acetate/hexanes) to give thedesired product (2.7 g, 80%). ¹H-NMR: 300 MHz, (CDCl₃) δ 7.98 (d, 1H),7.60 (d, 1H), 7.58 (s, 1H), 7.53 (dd, 1H), 7.38 (dd, 1H), 6.05 (s, 1H),2.48 (s, 3H).

Preparation of1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-ol(5D): 1-Bromo-3-methylnaphthalen-2-ol (5B) (340 mg, 1.43 mmol),2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid TFA salt (5C) (566mg, 1.72 mmol), Pd(PPh₃)₄ (166 mg, 0.14 mmol) and K₂CO₃ (991 mg, 7.15mmol) were added to a degassed solution of DMA (6 mL) and water (2 mL)and heated to 110° C. in a microwave for 1 h. The reaction mixture wascooled, diluted with ethyl acetate and washed with saturated sodiumbicarbonate solution, brine and dried (MgSO₄), filtered, concentratedand purified by flash column chromatography (silica gel, ethylacetate/hexanes) to give 5D (136 mg, 29%). LCMS-ESf⁺ (m/z): [M+H]⁺ calcdfor C₂₂H₁₈NO₂: 328.38. Found: 328.2.

Preparation of1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yltrifluoromethanesulfonate (5E):1-(2,3-Dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-ol(5D) (136 mg, 0.415 mmol) was taken in 2 mL DCM at −78° C. and2,6-lutidine (72 μL, 0.622 mmol) was added to it, followed bytrifluoromethanesulfonic anhydride (210 μL, 1.24 mmol) and the reactionwas stirred at −78° C. for 1 h. The reaction was quenched by addingsaturated NaCl solution. The reaction was extracted with DCM, washedwith brine, and concentrated. The crude product was purified by flashchromatography (silica gel, ethyl acetate/hexanes) to provide thedesired product 5E (79 mg, 41%). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₃H₁₇F3NO₄S: 460.45. Found: 460.0.

Preparation of7-(3-methyl-2-vinylnaphthalen-1-yl)-2,3-dihydropyrano[4,3,2-de]quinoline(5F): A solution of1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yltrifluoromethanesulfonate(5E) (89 mg, 0.194 mmol), tributyl(vinyl)tin (0.23 mL, 0/776 mmol),Pd(PPh₃)₄ (34 mg, 0.029 mmol) and LiCl (16 mg, 0.39 mmol) in dioxane (3mL) was stirred at 110° C. under Ar for 5 hours. The reaction mixturewas cooled, diluted with ethyl acetate and washed with saturated NaHCO₃solution (2×), brine and dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, hexanes) to give 5Fas a white solid (74 mg, 91%). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₄H₂₀NO: 338.42. Found: 338.2.

Preparation of(1S)-1-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethane-1,2-diol(5G): Compound 5G was prepared in a similar manner as compound 3G ofExample 1, except that compound 5F was used instead of compound 3F:LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄H₂₂NO₃: 372.44. Found: 372.3.

Preparation of(S)-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyethylpivalate (5H): Compound 5H was prepared in a similar manner as compound3H of Example 1 except that compound 5G was used instead of compound 3G.The two atropisomers (compounds 5H and 6A) were separated at this stageand carried forward separately. LCMS-ESI⁺ (m/z): [M+H]calcd forC₂₉H₃₀NO₄: 456.6. Found: 456.1.

Preparation of(S)-2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethylpivalate (51): Compound 51 was prepared in a similar manner as compound3I of Example 1 except that compound 5H was used instead of compound 3H.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₃H₃₈NO₄: 512.7. Found: 512.1.

Preparation of(S)-2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethanol(5J): Compound 5J was prepared in a similar manner as compound 3J ofExample 1 except that compound 51 was used instead of compound 3I.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₃₀NO₃: 428.5. Found: 428.0.

Example 4(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (6D)

(2S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (6D) was prepared in an analogous manner as used for thepreparation of compound 5K of Example 3. ¹H-NMR: 300 MHz, (CD₃OD) δ 8.58(d, 1H), 7.83 (m, 2H), 7.66 (m, 2H), 7.38 (m, 2H), 7.17 (m, 1H), 6.80(m, 1H), 5.18 (s, 1H), 4.61 (m, 2H), 3.56 (dd, 2H), 2.63 (s, 3H), 0.84(s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₈NO₄: 442.5. Found:442.1.

Example 5(R)-2-tert-Butoxy-[3-methyl-1-(5-(trifluoromethyl)quinolin-8-yl)-naphthalen-2-yl]-aceticacid (7D) and(S)-2-tert-butoxy-2-((S)-3-methyl-1-(5-(trifluoromethyl)quinolin-8-yl)naphthalen-2-yl)aceticacid (7E).

(S)-2-tert-butoxy-2-((R)-3-methyl-1-(5-(trifluoromethyl)quinolin-8-yl)naphthalen-2-yl)aceticacid (7D) was prepared in a similar manner as compound 4K of Example 2.¹H-NMR: 400 MHz, (CD₃OD) δ: 9.02 (d, J=8.8 Hz, 1H), 8.83 (dd, J=4.8, 1.2Hz, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.99-7.88 (m, 3H), 7.77 (d, J=7.6 Hz,1H), 7.45 (dd, J=8.0, 7.2 Hz, 1H), 7.20 (dd, J=8.0, 7.2 Hz, 1H), 6.83(d, J=8.4 Hz, 1H), 5.29 (s, 1H), 2.78 (s, 3H), 0.75 (s, 9H); ¹⁹F-NMR:376 MHz, (CD₃OD) δ: −60.81; LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₇H₂₅F3NO₃: 468.5. Found: 468.0.

(S)-2-tert-butoxy-2-((S)-3-methyl-1-(5-(trifluoromethyl)quinolin-8-yl)naphthalen-2-yl)aceticacid (7E) was prepared in a similar manner as compound 4L of Example 2.¹H-NMR: 400 MHz, (CD₃OD) δ: 8.82 (d, J=8.4 Hz, 1H), 7.72 (d, J=5.2, 1H),8.26 (d, J=7.6 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.89-7.73 (m, 3H), 7.40(dd, J=7.6, 7.2 Hz, 1H), 7.14 (dd, J=7.6, 7.2 Hz, 1H), 6.76 (d, J=8.4Hz, 1H), 5.06 (s, 1H), 2.70 (s, 3H), 0.75 (s, 9H); ¹⁹F-NMR: 376 MHz,(CD₃OD) δ: −60.87; LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₇H₂₅F₃NO₃: 468.5.Found: 468.0.

Example 6(S)-2-tert-Butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid(8)

Preparation of(S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)ethanol:

Preparation of(S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)ethanol:(S)-2-tert-Butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)ethyl pivalate(4G, 1.72 g, 4.56 mmol) was dissolved in MeOH (10 mL) and THF (10 mL).Sodium hydroxide (2 M, 9.13 mL) was added and the reaction mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate and washed with brine. The aqueous layer wasback-extracted with ethyl acetate and the combined organics were dried(MgSO₄), concentrated in vacuo and purified by flash columnchromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give acolorless liquid (1.12 g, 84%). ¹H-NMR: 300 MHz, (CD₃OD) δ: 8.23 (d,1H), 7.78 (d, 1H), 7.60 (s, 1H), 7.52 (dd, 2H), 5.69 (m, 1H), 3.83 (dd,1H), 3.61 (m, 1H), 2.71 (s, 3H), 1.18 (s, 9H).

Preparation of(S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetic acid: Theperiodic acid/chromium trioxide stock solution (26 mL) was added to asolution of(S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)ethanol (1.12 g,3.83 mmol) in wet acetonitrile (50 mL) (0.75% H₂O) at 0° C. The reactionmixture was stirred for 2 hours at 0° C. and quenched with 1.5 M K₂HPO₄solution. Ethyl acetate was added and organic layer separated and washedwith 1:1 brine/H₂O (2×), then saturated NaHSO₃/brine. The organic layerwas dried (MgSO₄), and concentrated and purified by flash columnchromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give awhite solid (0.9 g, 78%). ¹H-NMR: 300 MHz, (CDCl₃) δ: 8.24 (d, 1H), 7.73(d, 1H), 7.56 (m, 3H), 6.22 (br, 1H), 2.57 (s, 3H), 1.23 (s, 9H).LCMS-ESI⁻ (m/z): [M−H]⁻ calcd for C₁₇H₁₈ClO₃: 305.78. Found: 304.9,306.9.

Preparation of (S)-ethyl2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate: Ethyl iodide(0.35 mL, 1.5 eq.) was added to a mixture of(S)-2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetic acid (900mg, 2.93 mmol, 1 eq.) and Cs₂CO₃ (1.91 g, 2 eq.) in DMF (920 mL) at roomtemperature. The reaction mixture was stirred for 1 hour at roomtemperature. Ethyl acetate was added and organic layer separated andwashed with brine (2×). The organic layer was dried (MgSO₄) andconcentrated and purified by flash column chromatography (silica gel, 0to 100% ethyl acetate/hexanes) to give a colorless oil (0.911 g, 93%).¹H-NMR: 300 MHz, (CDCl₃) δ: 8.23 (d, 1H), 7.62 (d, 1H), 7.63 (s, 1H),7.46 (m, 3H), 6.10 (s, 1H), 4.06 (dd, 2H), 2.42 (s, 3H), 1.18 (s, 9H),1.08 (t, 3H).

Preparation of(S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid(8): A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (15 mg, 0.045mmol, 1 eq.), cyclohexenylboronic acid (9 mg, 1.5 eq.), Sphosprecatalyst (5 mg, 15%) and potassium phosphate (29 mg, 3 eq.), THF (0.2mL) and water (0.2 mL) was added and mixture sparged with nitrogen for10 minutes and then heated in microwave at 110° C. for 1 hour. Thereaction mixture was diluted with ethyl acetate and washed with brine,dried (MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give(S)-ethyl2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetate (8 mg).Analytical HPLC (Gemini, 2-98% ACN/H₂O+0.05% TFA, 10 minutes run): t_(R)(min)=7.06.

A solution of above intermediate (S)-ethyl2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetate (8 mg,0.021 mmol, 1 eq.) in ethanol (1.5 mL) and 1 N sodium hydroxide (0.42mL, 20 eq.) was heated at 60° C. overnight. The reaction mixture wasdiluted with ethyl acetate and washed with brine. The aqueous layer wasback-extracted with ethyl acetate and the combined organic layer wasdried (MgSO₄), filtered, concentrated and purified by reverse phase HPLC(Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Product lyophilized to give 8 as awhite powder (4.4 mg). Analytical HPLC (Gemini, 2-98% ACN/H₂O+0.05% TFA,10 minutes run): t_(R) (min)=6.10. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.83 (m,1H), 7.70 (m, 1H), 7.54 (m, 1H), 7.40 (m, 2H), 5.82, 5.62 (s, s, 1H),2.58 (m, 3H), 2.62-2.16 (m, 4H), 1.92-1.80 (m, 4H), 1.03 (m, 9H).LCMS-ESI (m/z): [M−H]⁻ calcd for C₂₃H₂₇O₃: 351.46. Found: 351.1.

Example 7(S)-2-tert-Butoxy-2-(1-((R)-6-fluoroquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (9)

Preparation of(S)-2-tert-butoxy-2-(1-((R)-6-fluoroquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (9):(S)-2-tert-butoxy-2-(1-((R)-6-fluoroquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (9) was prepared following the procedure to make(S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acidof Example 6 except that 6-fluoroquinolin-8-ylboronic acid was usedinstead of cyclohexenylboronic acid. Atropisomers were separated byflash column chromatography. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.81 (d, J=8.2Hz, 1H), 8.62 (dd, J=4.7 Hz, 1H), 8.02 (m, 1H), 7.96 (m, 1H), 7.82 (m,2H), 7.76 (m, 1H), 7.42 (dd, J=7.5 Hz, 1H), 7.20 (dd, J=7.8 Hz, 1H),6.84 (d, J=8.6 Hz, 1H), 5.18 (s, 1H), 2.72 (s, 3H), 0.82 (s, 9H).¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.9, −113.1. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₆H₂₅FNO₃: 418.48. found: 418.11.

Example 8(2S)-2-tert-Butoxy-2-(1-(5-fluoroquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (10)

Preparation of(2S)-2-tert-butoxy-2-(1-(5-fluoroquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (10):(2S)-2-tert-Butoxy-2-(1-(5-fluoroquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (10) was prepared following the procedure to make(S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acidof Example 6 except 5-fluoroquinolin-8-ylboronic acid was used insteadof cyclohexenylboronic acid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.81 (d, J=8.2Hz, 1H), 8.70 (dd, J=3.3 Hz, J=4.7 Hz, 1H), 8.09 (t, J=6.2 Hz, 1H), 7.92(m, 2H), 7.78 (m, 1H), 7.63 (t, J=9.0 Hz, 1H), 7.42 (t, J=7.0 Hz, 1H),7.18 (t, J=7.8 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 5.18 (s, 1H), 2.68 (s,3H), 0.80 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.9, −123.2. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₆H₂₅FNO₃: 418.47. found: 418.1.

Example 9(S)-2-tert-Butoxy-2-(1-(3,3-dimethyl-6-oxocyclohex-1-enyl)-3-methylnaphthalen-2-yl)aceticacid (11)

Preparation of(S)-2-tert-butoxy-2-(1-(3,3-dimethyl-6-oxocyclohex-1-enyl)-3-methylnaphthalen-2-yl)aceticacid (11):(S)-2-tert-Butoxy-2-(1-(3,3-dimethyl-6-oxocyclohex-1-enyl)-3-methylnaphthalen-2-yl)aceticacid (11) was prepared following the procedure to make(S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acidof Example 6 except that4,4-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enonewas used instead of cyclohexenylboronic acid. Atropisomers wereseparated by flash column chromatography. ¹H-NMR: 400 MHz, (CD₃OD) δ:7.72 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.39 (m, 2H), 7.37 (m, 1H), 7.02(s, 1H), 5.42 (s, 1H), 2.82 (m, 1H), 2.67 (m, 1H), 2.58 (s, 3H), 2.18(m, 2H), 1.38 (s, 6H), 1.08 (s, 9H). LCMS-ESI⁺ (m/z): [M−H]⁻ calcd forC₂₅H₂₉O₄: 393.50. found: 393.0.

Example 10(S)-2-tert-Butoxy-2-(1-cyclopentenyl-3-methylnaphthalen-2-yl)acetic acid(12)

Preparation of(S)-2-tert-butoxy-2-(1-cyclopentenyl-3-methylnaphthalen-2-yl)acetic acid(12):(S)-2-tert-Butoxy-2-(1-cyclopentenyl-3-methylnaphthalen-2-yl)acetic acid(12) was prepared following the procedure to make(S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acidof Example 6, except that cyclopentenylboronic acid was used instead ofcyclohexenylboronic acid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.78 (m, 1H), 7.53(s, 1H), 7.40 (m, 2H), 6.10-5.54 (m, 3H), 2.90 (m, 1H), 2.65 (m, 5H),2.57 (s, 3H), 1.18 (s, 9H). LCMS-ESI⁻ (m/z): [M−H]-calcd for C₂₂H₂₅O₃:337.44. found: 337.1.

Example 11(2S)-2-tert-Butoxy-2-(3-methyl-1-(4-methylcyclohex-1-enyl)naphthalen-2-yl)aceticacid (13)

Preparation of(2S)-2-tert-butoxy-2-(3-methyl-1-(4-methylcyclohex-1-enyl)naphthalen-2-yl)aceticacid (13):(2S)-2-tert-Butoxy-2-(3-methyl-1-(4-methylcyclohex-1-enyl)naphthalen-2-yl)aceticacid was prepared following the procedure to make(S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acidof Example 6, except that 4-methylcyclohex-1-enylboronic acid was usedinstead of cyclohexenylboronic acid. ¹H-NMR: 400 MHz, (CD₃OD) δ:7.92-7.78 (m, 1H), 7.70 (m, 1H), 7.52 (s, 1H), 7.39 (m, 2H), 6.10-5.58(m, 2H), 2.56 (s, 3H), 2.65-1.84 (m, 6H), 1.50 (m, 1H), 1.22 (s, 9H),1.14 (t, 3H). LCMS-ESF (m/z): [M−H]⁻ calcd for C₂₄H₂₉O₃: 365.49. found:365.1.

Example 12(S)-2-tert-Butoxy-2-(1-(4,4-dimethylcyclohex-1-enyl)-3-methylnaphthalen-2-yl)aceticacid (14)

Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4,4-dimethylcyclohex-1-enyl)-3-methylnaphthalen-2-yl)acetate:To a solution of (S)-ethyl2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (74 mg, 0.22mmol) and2-(4,4-dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(78 mg, 0.33 mmol) in tetrahydrofuran (2 mL) was added potassiumphosphate (153 mg, 0.66 mmol) and(2-dicyclohexyl-phosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II)chloride methyl-t-butyl ether adduct, (SPhos) palladium(II)phenethylamine chloride (15 mg, 0.022 mmol) and the reaction wasdegassed 10 minutes with argon. The reaction was heated to 110° C. for 1hour in a microwave reactor. The crude reaction was absorbed onto silicaand purified by flash column chromatography (silica gel, ethylacetate/hexanes) to give a clear white oil (36 mg). ¹H-NMR: 400 MHz,(CDCl₃) δ: 7.83-7.78 (m, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.53 (s, 1H),7.43-7.36 (m, 2H), 5.66-5.61 (m, 2H), 4.20-4.03 (m, 2H), 2.66-2.60 (m,2H), 2.26-2.03 (m, 4H), 1.87-1.59 (m, 5H), 1.24-1.20 (m, 9H), 1.19-1.11(m, 6H).

Preparation of(S)-2-tert-butoxy-2-(1-(4,4-dimethylcyclohex-1-enyl)-3-methylnaphthalen-2-yl)aceticacid (14): To a solution of (S)-ethyl2-tert-butoxy-2-(1-(4,4-dimethylcyclohex-1-enyl)-3-methylnaphthalen-2-yl)acetate(36 mg, 0.087 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 5 mL) wasadded lithium hydroxide (21 mg, 0.88 mmol) and the reaction was heatedto 35° C. overnight. The reaction was then heated to 45° C. for 2 hours,and subsequently 5 equivalents of lithium hydroxide was added, and thereaction stirred at room temperature over 2 days. The reaction was thenheated to 50° C. overnight. The crude reaction was purified by reversephase HPLC (Gemini, 20-100% ACN/H₂O+0.1% TFA). Product was lyophilizedto give a white powder (8.6 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.82 (d,J=8.0 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.54 (s, 1H), 7.39 (m, 2H), 5.66(m, 2H), 2.66 (m, 1H), 2.58 (s, 3H), 2.13 (m, 3H), 1.64 (m, 2H), 1.23(s, 9H), 1.16 (s, 3H), 1.14 (s, 3H). LCMS-ESI⁻ (m/z): [M−H]⁻ calcd forC₂₅H₃₁O₃: 379.24. found: 379.27.

Example 13(S)-2-tert-Butoxy-2-(3-methyl-1-(spiro[2.5]oct-5-en-6-yl)naphthalen-2-yl)aceticacid (15)

Preparation of(S)-2-tert-butoxy-2-(3-methyl-1-(spiro[2.5]oct-5-en-6-yl)naphthalen-2-yl)aceticacid (15):(S)-2-tert-butoxy-2-(3-methyl-1-(spiro[2.5]oct-5-en-6-yl)naphthalen-2-yl)aceticacid was prepared following the procedure for(S)-2-tert-butoxy-2-(1-(4,4-dimethylcyclohex-1-enyl)-3-methylnaphthalen-2-yl)aceticacid of Example 12 except using4,4,5,5-tetramethyl-2-(spiro[2.5]oct-5-en-6-yl)-1,3,2-dioxaborolaneinstead of2-(4,4-dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand that in the final step the reaction was heated to 50° C. overnightfollowed by an addition of 10 equivalents of lithium hydroxide andheating to 60° C. for four hours and then at 45° C. overnight. ¹H-NMR:400 MHz, (CD₃OD) δ: 7.90 (d, J=7.6 Hz, 1H), 7.71 (br d, J=7.2 Hz, 1H),7.53 (d, J=8.0 Hz, 1H), 7.40 (m, 2H), 5.88 (s, 1H), 5.70 (s, 1H), 2.73(m, 1H), 2.78 (s, 3H), 2.31 (m, 2H), 2.09 (m, 1H), 1.73 (m, 1H), 1.59(m, 1H), 1.24 (s, 9H), 0.49 (m, 4H). LCMS-ESI (m/z): [M−H]-calcd forC₂₅H₂₉O₃: 377.22. found: 377.34.

Example 14(S)-2-tert-Butoxy-2-(3-methyl-1-(quinolin-3-yl)naphthalen-2-yl)aceticacid (16)

Preparation of(S)-2-tert-butoxy-2-(3-methyl-1-(quinolin-3-yl)naphthalen-2-yl)aceticacid (16):(S)-2-tert-Butoxy-2-(3-methyl-1-(quinolin-3-yl)naphthalen-2-yl)aceticacid (16) was prepared following the procedure to make(S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acidof Example 6, using quinolin-3-ylboronic acid instead ofcyclohexenylboronic acid. The compound is an atropisomer mixture.¹H-NMR: 400 MHz, (CD₃OD) δ: 9.20-8.50 (m, 2H), 8.18 (m, 1H), 8.08 (m,1H), 7.95 (m, 1H), 7.80 (m, 3H), 7.40 (t. 1H), 7.25 (t, 1H), 7.06 (m,1H), 5.19 (s, 1H), 2.62 (d, 3H), 0.95, 0.86 (s, 9H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₆H₂₆NO₃: 400.48. found: 400.2.

Example 15(S)-2-(tert-Butoxy)-2-((S)-1-(7-fluoro-2-methylquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (17)

Preparation of(S)-2-(tert-butoxy)-2-((S)-1-(7-fluoro-2-methylquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (17):(S)-2-(tert-butoxy)-2-((S)-1-(7-fluoro-2-methylquinolin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (17) was prepared following the procedure used to prepare compound4K except that 7-fluoro-2-methylquinolin-8-ylboronic acid was usedinstead of compound 4H. ¹H NMR (400 MHz, CD₃OD) δ 9.09 (d, J=8.5 Hz,1H), 8.51 (dd, J=9.1, 5.6 Hz, 1H), 8.01 (s, 1H), 7.95 (d, J=8.1 Hz, 1H),7.92-7.76 (m, 2H), 7.58-7.43 (m, 1H), 7.30 (ddd, J=8.2, 6.9, 1.2 Hz,1H), 6.97 (d, J=8.6 Hz, 1H), 5.17 (s, 1H), 2.80 (s, 3H), 2.79 (s, 3H),0.87 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₇H₂₇FNO₃: 432.5.found: 432.1.

Example 16 (S)-Ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(18)

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(18): A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (compound ofExample 6) (116 mg, 0.348 mmol),2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl salt (96 mg,0.383 mmol), Sphos precatalyst (35 mg, 0.0522 mmol), cesium fluoride(233 mg, 1.54 mmol) and flushed with nitrogen. Dimethoxyethane (3.0 mL,distilled from Na/benzophenone) was added and mixture was heated inmicrowave at 120° C. for 1.5 hour. The reaction mixture was diluted withethyl acetate and washed with brine. The aqueous layer wasback-extracted and combined organic layer dried (MgSO₄), filtered,concentrated and purified by reverse phase HPLC (Gemini, 5 to 100%acetonitrile/H₂O+0.1% TFA) to give a yellow powder (16.8 mg). ¹H-NMR:400 MHz, (CD₃Cl) δ: 8.93 (d, J=4.4 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.82(s, 1H), 7.81 (d, J=8.8 Hz, 1H), 7.45-7.35 (m, 3H), 7.13 (dd, J=7.2, 7.2Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 5.16 (s, 1H), 4.68-4.65 (m, 2H),3.98-3.86 (m, 2H), 3.52 (q, J=5.6 Hz, 2H), 2.69 (s, 3H), 1.34 (t, J=7.2Hz, 3H), 0.86 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₂NO₄:470.5. found: 470.1.

Example 17(S)-2-(1-(3-(Azetidin-1-yl)phenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (19)

Preparation of 1-(3-bromophenyl)azetidine: A mixture of 1,3-bromobenzene(1.0 g, 4.24 mmol), azetidine (0.19 mL, 2.83 mmol), Pd₂(dba)₃ (0.129 g,0.142 mmol), Xantphos (0.164 g, 0.283 mmol), and sodium tert-butoxide(0.816 g, 8.49 mmol) in dioxane (20 mL) was sparged with nitrogen for 15minutes. The reaction mixture was heated at 100° C. for 3 hours and thencooled to room temperature. The resulting mixture was diluted with waterand ethyl acetate and washed with water (2×), brine, dried (MgSO₄),filtered, concentrated and purified by flash column chromatography(silica gel, 0 to 20% ethyl acetate/hexanes) to give a yellow oil(0.4474 g). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₉H₁₁BrN: 213.1. found:212.0, 214.0.

Preparation of1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine: Amixture of 1-(3-bromophenyl)azetidine (0.4474 g, 2.11 mmol),bis-pinacolatodiboron (0.803 g, 3.16 mmol), Pd(dppf)Cl₂ (0.172 g, 0.211mmol), and potassium acetate (0.621 g, 6.33 mmol) in dioxane (21 mL) wassparged with nitrogen for 30 minutes. The reaction mixture was heated at90° C. for 1.5 hours. The reaction was cooled to room temperature,diluted with ethyl acetate and washed with brine, dried (MgSO₄),filtered, concentrated and purified by flash column chromatography(silica gel, 0 to 20% ethyl acetate/hexanes) to give a yellow wax(0.6474 g). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₁₅H₂₃BNO₂: 260.2. found:260.1.

Preparation of (S)-ethyl2-(1-(3-(azetidin-1-yl)phenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (60.5 mg,0.181 mmol),1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine (93.7mg, 0.361 mmol),chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]Pd(II)methyl-t-butylether adduct (12.2 mg, 0.0181 mmol) and potassium phosphate (153 mg,0.543 mmol), THF (2 mL) and water (1 mL) was added and mixture spargedwith nitrogen for 10 minutes and then heated in microwave at 110° C. for1 hour. The reaction mixture was diluted with ethyl acetate and washedwith brine, dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, ethyl acetate/hexanes) to the desiredproduct containing some impurities that was used in the next stepwithout further purification.

Preparation of(S)-2-(1-(3-(azetidin-1-yl)phenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (19): The above residue containing (S)-ethyl2-(1-(3-(azetidin-1-yl)phenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetatein THF (1.0 mL), MeOH (0.1 mL) and 5 M NaOH (0.1 mL) was heated at 45°C. for 18 hours. The reaction mixture was concentrated, diluted withethyl acetate and water and washed with saturated ammonium chloridesolution. The aqueous layer was back-extracted with ethyl acetate andthe combined organic layer was dried (MgSO₄), filtered, concentrated andpurified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Theproduct was lyophilized to give a white powder (4.6 mg) which wasresubjected to reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA).Product containing fractions were stirred with saturated sodiumbicarbonate solution for 30 minutes. The mixture was extracted withethyl acetate (3×), dried (MgSO₄), filtered, concentrated andlyophilized from acetonitrile/water to give an atropisomer mixture as awhite powder (1.9 mg). ¹H NMR (400 MHz, CD₃OD) δ 7.81-7.67 (m, 1H), 7.62(s, 0.6H), 7.60 (s, 0.4H), 7.4-7.18 (m, 4H), 6.78 (s, 0.5H), 6.70 (d,J=7.7 Hz, 0.5H), 6.64-6.57 (m, 1H), 5.32 (s, 0.6H), 5.30 (s, 0.4H),3.90-3.83 (m, 3H), 2.60 (s, 3H), 2.40-2.35 (m, 2H), 0.99 (s, 4H), 0.97(s, 5H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₆H₃₀NO₃: 404.5. found:404.1.

Example 18(2S)-2-tert-Butoxy-2-(1-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (20)

Preparation of(2S)-2-tert-butoxy-2-(1-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (20):(S)-2-tert-Butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (130 mg) was dissolved in 20 mL EtOH and 1 drop of HOAc was addedto the solution. 10% Pt/C (30 mg) was added the reaction was stirred atroom temperature under one atmosphere of hydrogen (balloon) overnight.The reaction mixture was filtered, diluted with ethyl acetate and washedwith brine, dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 20% MeOH/DCM) to give(2S)-2-tert-butoxy-2-(1-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (130 mg). 8 mg of the material was purified by reverse phase HPLC(Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Product lyophilized to give awhite powder (5.5 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.78 (d, J=8.2 Hz,1H), 7.63 (s, 1H), 7.40 (m, 2H), 7.27 (m, 1H), 6.70 (d, J=8.21 Hz, 1H),6.22 (d, J=8.21 Hz, 1H), 5.26 (s, 1H), 4.41 (m, 1H), 4.22 (m, 1H), 3.18(m, 2H), 2.83 (m, 1H), 2.59 (s, 3H), 2.12 (m, 1H), 1.98 (m, 1H), 1.70(m, 1H), 1.32 (m, 1H), 1.05 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₈H₃₂NO₄: 446.55. found: 446.1.

Example 19 (2S)-Methyl 2-tert-butoxy-2-(1-((7R)-2,3,3a,4,5,6

Preparation of (2S)-methyl2-tert-butoxy-2-(1-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(21): At 0° C., NaH (60%, 5 mg) was added to(2S)-2-tert-butoxy-2-(1-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (26 mg, 0.06 mmol, 1 eq.) in 1.5 mL DMF at 0° C. After stirring for30 minutes, MeI (50 μL, excess) was added to the solution. The reactionwas stirred at 0° C. for 1 h. The reaction mixture was concentrated invacuo and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1%TFA). The product was lyophilized to give (2S)-methyl2-tert-butoxy-2-(1-((7R)-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetateas white powder (11 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.78 (d, J=8.2 Hz,1H), 7.63 (s, 1H), 7.42 (m, 1H), 7.32 (m, 2H), 6.70 (m, 1H), 6.34 (d,1H), 5.26 (s, 1H), 4.41 (m, 1H), 4.22 (m, 1H), 3.72 (s, 3H), 3.22 (m,2H), 2.91 (m, 1H), 2.59 (s, 3H), 2.18 (m, 1H), 2.08 (m, 1H), 1.72 (m,1H), 1.39 (m, 1H), 1.05 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₉H₃₄NO₄: 460.58. found: 460.1.

Example 20(2S)-2-tert-Butoxy-2-(3-methyl-1-((7R)-6-methyl-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)aceticacid (22)

Preparation of(R)-7-(2-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-3-methylnaphthalen-1-yl)-6-methyl-2,3-dihydropyrano[4,3,2-de]quinolin-6-iumiodide: A mixture of MeI (0.8 mL, large excess) and (S)-ethyl2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(37 mg). The reaction was heated at 50° C. for 2 days. The reactionmixture was diluted with ethyl acetate and washed with brine, dried overMgSO₄, filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 20% MeOH/DCM) to give the desiredmaterial as a green oil (50 mg). LCMS-ESI⁺ (m/z): [M]⁺ calcd forC₃₄H₃₄NO₄: 484.61. found: 484.3.

Preparation of (2S)-ethyl2-tert-butoxy-2-(3-methyl-1-((7R)-6-methyl-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetate:(R)-7-(2-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-3-methylnaphthalen-1-yl)-6-methyl-2,3-dihydropyrano[4,3,2-de]quinolin-6-iumiodide (50 mg) was dissolved in 20 mL EtOH and 1 drop of HOAc was addedto the solution. 10% Pt/C (30 mg) was added and the resulting reactionmixture was stirred under hydrogen (1 atm, balloon) at room temperatureovernight. The reaction mixture was filtered and diluted with ethylacetate and washed with brine, dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, 0 to 20% MeOH/DCM)to give (2S)-ethyl2-tert-butoxy-2-(3-methyl-1-((7R)-6-methyl-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetateas a grey solid (15 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₁H₃₈NO₄:488.63. found: 488.2.

Preparation of(2S)-2-tert-butoxy-2-(3-methyl-1-((7R)-6-methyl-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)aceticacid (22): To a solution of (2S)-ethyl2-tert-butoxy-2-(3-methyl-1-((7R)-6-methyl-2,3,3a,4,5,6-hexahydro-pyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)acetate(12 mg, 0.021 mmol) in ethanol (1 mL) was added 2 N sodium hydroxide (1mL) and the resulting reaction mixture was heated at 80° C. overnight.The reaction mixture was then concentrated and purified by reverse phaseHPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). The product was lyophilizedto give(2S)-2-tert-butoxy-2-(3-methyl-1-((7R)-6-methyl-2,3,3a,4,5,6-hexahydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)aceticacid (22) as a white powder (2.6 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.82(d, J=8.2 Hz, 1H), 7.67 (s, 1H), 7.43 (m, 2H), 7.38 (m, 1H), 6.92 (m,1H), 6.71 (m, 1H), 5.06 (s, 1H), 4.41 (m, 1H), 4.28 (m, 1H), 3.52 (m,1H), 3.04 (m, 2H), 2.67, 2.62 (s, s, 3H), 2.29 (s, 3H), 2.28 (m, 1H),2.08 (m, 1H), 1.72 (m, 1H), 1.59 (m, 1H), 0.95 (s, 9H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₉H₃₄NO₄: 460.58. Found: 461.3.

Example 217-((R)-2-((S)-tert-Butoxy(carboxy)methyl)-3-methylnaphthalen-1-yl)-2,3-dihydropyrano[4,3,2-de]quinoline6-oxide (23)

Preparation of7-((R)-2-((S)-1-tert-butoxy-2-hydroxyethyl)-3-methylnaphthalen-1-yl)-2,3-dihydropyrano[4,3,2-de]quinoline6-oxide: To a solution of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)ethanol(6C, 31 mg, 0.727 mmol) in dichloromethane (1.3 mL) was added3-chloroperoxybenzoic acid (77%, 36 mg, 0.161 mmol) and reaction mixturewas stirred for 7 hours. Additional 3-chloroperoxybenzoic acid (26 mg,0.116 mmol) was added and reaction mixture was stirred overnight andquenched with saturated sodium thiosulfate solution. The resultingmixture was extracted with ethyl acetate, washed with saturated sodiumbicarbonate solution, brine, dried (MgSO₄), filtered, concentrated andpurified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Theproduct was lyophilized to give a yellow powder (4.7 mg). LCMS-ESI⁺(m/z): [M]⁺ calcd for C₂₈H₃₀NO₄: 443.5. found: 443.9.

Preparation of7-((R)-2-((S)-tert-butoxy(carboxy)methyl)-3-methylnaphthalen-1-yl)-2,3-dihydropyrano[4,3,2-de]quinoline6-oxide (23): To a solution of7-((R)-2-((S)-1-tert-butoxy-2-hydroxyethyl)-3-methylnaphthalen-1-yl)-2,3-dihydropyrano[4,3,2-de]quinoline6-oxide (4.7 mg, 0.0106 mol) in wet acetonitrile (0.75% H₂O, 1 mL) wasadded Hs₅₁₀dCrO₃ stock solution (0.439 M, 0.1 mL, 0.423 mmol) was addedat 0° C. The reaction mixture was stirred for 90 minutes at roomtemperature and additional HsIOdCrO₃ stock solution (0.439 M, 0.1 mL)was added. After stirring for 90 minutes, the reaction mixture wasquenched with saturated NaHCO₃ solution and extracted with ethyl acetate(2×). The organic layer was washed with H₂O, saturated NaHSO₃ solution,dried (MgSO₄), filtered, concentrated and purified by reverse phase HPLC(Gemini, 5 to 100% acetonitrile/H₂O+0.1% TFA) to give a yellow powder(1.2 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.51 (d, J=6.3 Hz, 1H), 7.79 (d,J=8.2 Hz, 1H), 7.69 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.44 (d, J=6.1 Hz,1H), 7.43-7.37 (m, 1H), 7.34 (d, J=8.3 Hz, 1H), 7.25-7.13 (m, 1H), 6.87(d, J=7.8 Hz, 1H), 5.06 (s, 1H), 4.67-4.55 (m, 2H), 3.52-3.46 (m, 2H),2.61 (s, 3H), 0.97 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₈NO₅:458.5. found: 458.1.

Example 22(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-(dimethylaminomethyl)naphthalen-2-yl)acetic acid (24)

Preparation of(S)-ethyl2-(3-(bromomethyl)-1-(4-chlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate:To a solution of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetate (3K,43 mg, 0.0105 mmol) in CCl₄ (2 mL) was added NBS (24 mg, 0.13 mmol) andAIBN (cat. amount). The reaction mixture was refluxed for 5 h. Aftercooling to room temperature, the reaction mixture was diluted by DCM,washed with sat. NaHCO₃, extracted with DCM and the organic layers werecombined and dried over MgSO₄, filtered, concentrated and purified byflash column chromatography (silica gel, ethyl acetate/hexanes) toprovide 12 mg of the desired product. ¹H-MNR 400 MHz (CDCl₃) δ: 8.01 (s,1H), 7.77 (d, J=4 Hz, 1H), 7.43-7.15 (m, 7H), 5.11 (d, J=5.2 Hz, 1H),5.06 (s, 1H), 5.00 (d, J=5.2 Hz, 1H), 4.07-4.02 (m, 2H), 1.20-1.15 (m,3H), 0.96 (s, 9H).

Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-((dimethyl-amino)methyl)naphthalen-2-yl)acetate:To a solution of (S)-ethyl2-(3-(bromomethyl)-1-(4-chlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetate(12 mg, 0.0245 mmol) in THF (1 mL) was added dimethylamine (2 M in THF,0.12 μL). The reaction mixture was stirred at room temperature for 1 h.Removal of the solvent in vacuo followed by purification of the residueby flash chromatography (silica gel, ethyl acetate/hexanes) provided 8mg of the desired product. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₇H₃₃ClNO₃: 454.2. Found: 454.2, 456.1.

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-((dimethyl-amino)methyl)naphthalen-2-yl)aceticacid (24): To a solution of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-((dimethylamino)methyl)naphthalen-2-yl)acetatein THF (0.5 mL) and MeOH (0.5 mL), was added NaOH solution (2N, 100 μL).The reaction mixture was stirred at room temperature for 1 day. Thereaction mixture was neutralized by HOAc and concentrated down. Theresidue was dissolved in MeOH and purified by reverse phase HPLC(Gemini, 5 to 100% ACN/H₂O+0.1% TFA) to provide the desired product (3.7mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.12 (s, 1H), 8.00 (d, J=4.2 Hz, 1H),7.65-7.52 (m, 5H), 7.32-7.30 (m, 2H), 5.36 (s, 1H), 4.93 (d, J=6.8 Hz,1H), 4.47 (d, J=7 Hz, 1H), 3.12 (s, 3H), 2.89 (s, 3H), 1.12 (s, 9H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₅H₂₉C1NO₃: 426.2. Found: 426.1,428.1.

Example 23(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-((pyridin-3-yloxy)methyl)naphthalen-2-yl)aceticacid (25)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-((pyridin-3-yloxy)methyl)naphthalen-2-yl)aceticacid (25):(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-((pyridin-3-yloxy)methyl)naphthalen-2-yl)aceticacid (25) was prepared by the similar method of Example 22, except thatK₂CO₃ and pyridin-3-ol were used instead of dimethylamine in step 2.¹H-NMR: 400 MHz, (CD₃OD) δ: 8.39 (d, J=2.8 Hz, 1H), 8.31 (s, 1H), 8.05(s, 1H), 7.96-7.86 (m, 3H), 7.64-7.49 (m, 5H), 7.34-7.31 (m, 2H), 6.44(d, J=7.4 Hz, 1H), 6.12 (d, J=7.6 Hz, 1H), 5.24 (s, 1H), 0.92 (s, 9H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇ClNO₄: 476.2. Found: 476.0,478.0.

Example 24(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-((pyrimidin-5-yloxy)methyl)naphthalen-2-yl)aceticacid (26)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-((pyrimidin-5-yloxy)methyl)naphthalen-2-yl)aceticacid (26):(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-((pyrimidin-5-yloxy)methyl)naphthalen-2-yl)aceticacid (26) was prepared by the similar method of Example 22, except thatK₂CO₃ and pyrimidin-5-ol were used instead of dimethylamine in step 2.¹H-NMR: 400 MHz, (CD₃OD) δ: 8.75 (s, 1H), 8.60 (s, 1H), 8.08 (s, 1H),7.88 (d, J=3.8 Hz, 1H), 7.60 (s, 2H), 7.58-7.26 (m, 4H), 5.72-5.70 (m,2H), 5.21 (s, 1H), 1.02 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₇H₂₆ClN₂O₄: 477.2. Found: 477.1, 478.1.

Example 25 (S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-(morpholinomethyl)naphthalen-2-yl)acetic acid (27)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-(morpholinomethyl)naphthalen-2-yl)aceticacid (27):(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-(morpholinomethyl)naphthalen-2-yl)aceticacid (27) was prepared by the similar method of Example 22, except thatmorpholine was used instead of dimethylamine in step 2. ¹H-NMR: 400 MHz,(CD₃OD) δ: 8.14 (s, 1H), 7.99 (d, J=4 Hz, 1H), 7.64-7.60 (m, 3H),7.53-7.49 (m, 2H), 7.29-7.27 (m, 2H), 5.38 (s, 1H), 4.81-4.78 (m, 2H),4.11-4.08 (m, 2H), 3.81-3.78 (m, 2H), 3.55-3.41 (m, 4H), 1.16 (s, 9H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₇H₃₁ClNO₄: 468.2. Found: 468.0,470.1.

Example 26 (S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-(methoxymethyl)naphthalen-2-yl)acetic acid (28)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-(methoxymethyl)naphthalen-2-yl)aceticacid (28):(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-(methoxymethyl)naphthalen-2-yl)aceticacid (28) was prepared by the similar method of Example 22, except thatsodium methoxide and methanol were used instead of dimethylamine and THFand the reaction was heated at 50° C. for 3 h. ¹H-NMR: 400 MHz, (CD₃OD)δ: 7.91 (s, 1H), 7.77 (d, J=4.2 Hz, 1H), 7.50-7.13 (m, 7H), 5.06 (s,1H), 4.84 (d, J=6.6 Hz, 2H), 4.71 (d, J=6.4 Hz, 2H), 3.32 (s, 3H), 0.90(s, 9H). LCMS-ESI⁺ (m/z): [M−H]⁺ calcd for C₂₄H₂₄ClO₄: 411.1. Found:411.0, 413.0.

Example 27(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)aceticacid (29A) and(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-ethylnaphthalen-2-yl)aceticacid (29B)

Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate: Toa solution of (S)-ethyl2-(3-(bromomethyl)-1-(4-chlorophenyl)naphthalen-2-yl)-2-tert-butoxyacetatefrom Example 22 (200 mg, 0.408 mmol) in acetonitrile (4 mL) was addedN-methylmorpholine N-oxide (478 mg, 4.08 mmol) and 4 Å molecular sieves(200 mg). The reaction mixture was stirred at room temperature for 2 h.Additional N-methylmorpholine N-oxide (500 mg, 4.27 mmol) was added andthe reaction mixture was stirred at room temperature for another 2 h.The reaction mixture was then filtered and the organics washed with sat.NaHCO₃, extracted by DCM, dried over MgSO₄. The organic layer was thenfiltered, concentrated down and purified by flash column chromatography(silica gel, ethyl acetate/hexanes) to provide 110 mg (64%) of thedesired product. ¹H-MNR 400 MHz (CDCl₃) δ: 10.82 (s, 1H), 8.55 (s, 1H),8.01 (d, J=4 Hz, 1H), 7.55-7.23 (m, 7H), 5.19 (s, 1H), 4.17-4.13 (m,2H), 1.22 (t, J=7 Hz, 3H), 1.04 (s, 9H).

Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)acetate: To asuspension of methyltriphenylphosphonium bromide (60 mg, 0.168 mmol) inTHF (1 mL) at −78° C. was added dropwise n-BuLi (1.6 M in hexanes, 90μL), followed after 30 min by a solution of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate (12mg, 0.028 mmol) in THF (1 mL). The reaction mixture was allowed to warmto room temperature and stirred at room temperature for 2 hours. Thismixture was added to another mixture, which was made by adding n-BuLi(1.6 M in hexanes, 300 μL) to a suspension of methyltriphenylphosphoniumbromide (200 mg, 0.56 mmol) in THF (2 mL) and stirred at −78° C. for 15min. Then the reaction mixture was allowed to warm to room temperatureand stirred at room temperature for 1 h. The reaction mixture wasdiluted with EtOAc, washed with sat. NH₄Cl, and extracted with EtOAc.The organic layers were combined, dried over MgSO₄, filtered,concentrated in vacuo and purified by flash column chromatography(silica gel, ethyl acetate/hexanes) to provide 7.4 mg of the desiredproduct. ¹H-MNR 400 MHz (CDCl₃) δ: 7.95 (s, 1H), 7.78 (d, J=4.2 Hz, 1H),7.57-7.50 (m, 1H), 7.43-7.17 (m, 6H), 5.62 (dd, J=8.1, 2 Hz, 1H), 5.25(dd, J=5.3, 1.8 Hz, 1H), 5.07 (s, 1H), 4.06-4.02 (m, 2H), 1.10 (t, J=7Hz, 3H), 0.93 (s, 9H).

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)aceticacid (29A): To a solution (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)acetate (7.4mg, 0.0175 mmol) in THF/MeOH (1/1, 1 mL), was added NaOH (2 N, 280 L).The reaction mixture was stirred at room temperature overnight. Then thetemperature was raised to 40° C. and the reaction mixture was stirredfor 4 h. The reaction was then cooled down and neutralized by addingHOAc. The reaction mixture was concentrated in vacuo and the residue waspurified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA) toprovide 5.3 mg of the desired product. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.07(s, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.60-7.54 (m, 4H), 7.48-7.44 (m, 1H),7.35-7.31 (m, 2H), 7.25-7.22 (m, 1H), 5.76-5.71 (m, 1H), 5.29-5.26 (m,1H), 5.21 (s, 1H), 0.98 (s, 9H). LCMS-ESI⁻ (m/z): [M−H]-calcd forC₂₄H₂₃ClO₃: 393.1. Found: 393.0.

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-ethylnaphthalen-2-yl)aceticacid (29B): To a solution of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-vinylnaphthalen-2-yl)aceticacid (4 mg, 0.010 mmol) in EtOH (1.5 mL) was added Rh/Al₂O₃ (cat.amount) and the resulting mixture stirred under hydrogen (1 atm,balloon) at room temperature for 2 h. The reaction mixture was filteredover Celite, concentrated in vacuo and the residue was purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA) to provide 0.8mg of the desired product. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.81 (d, J=4.2Hz, 1H), 7.77 (s, 1H), 7.58-7.53 (m, 3H), 7.44-7.41 (m, 1H), 7.33-7.20(m, 3H), 5.20 (s, 1H), 3.14-3.08 (m, 1H), 2.93-2.87 (m, 1H), 1.34 (t,J=7.4 Hz, 3H), 0.98 (s, 9H). LCMS-ESI⁻ (m/z): [M−H]⁻ calcd forC₂₄H₂₄ClO₃: 395.1. Found: 395.0.

Example 28(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-(hydroxymethyl)naphthalen-2-yl)aceticacid (30)

Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-(hydroxymethyl)naphthalen-2-yl)acetate:To a solution of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate (12mg, 0.0283 mmol) in DCM/EtOH (1/1, 1 mL) at 0° C., was added NaBH₄ (2mg, 0.053 mmol) and the reaction mixture stirred at 0° C. for 2 h. Thereaction was quenched by adding sat. NH₄Cl. The resulting mixture wasextracted with DCM, dried over MgSO₄, filtered, concentrated in vacuoand purified by flash column chromatography (silica gel, ethylacetate/hexanes) to provide 8 mg of the desired product. ¹H-MNR 400 MHz(CDCl₃) δ: 7.85 (s, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.46-7.38 (m, 4H),7.30-7.26 (m, 1H), 7.20-7.15 (m, 2H), 5.13 (s, 1H), 5.02 (d, J=6.2 Hz,1H), 4.54 (d, J=6 Hz, 1H), 4.12-4.02 (m, 2H), 3.82 (bs, 1H), 1.14 (t,J=7 Hz, 3H), 1.01 (s, 9H).

Preparation of (S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-(hydroxymethyl)naphthalen-2-yl)acetic acid (30): This compound was made using a methodsimilar to that used for(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-(dimethylaminomethyl)naphthalen-2-yl)acetic acid in Example 22. The compound was purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O). ¹H-NMR: 400 MHz, (CD₃OD)δ: 7.98 (s, 1H), 7.78 (d, J=4.2 Hz, 1H), 7.52-7.44 (m, 3H), 7.39-7.35(m, 1H), 7.26-7.13 (m, 3H), 5.09 (s, 1H), 5.05 (d, J=7.4 Hz, 1H), 4.73(d, J=7.2 Hz, 1H), 0.92 (s, 9H). LCMS-ESI⁻ (m/z): [M−H]calcd forC₂₃H₂₂ClO₄: 397.1. Found: 396.9, 399.0.

Example 29(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)aceticacid (31)

Preparation of(S)-2-((R)-3-(bromomethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)-2-tert-butoxyethylpivalate: The compound was made similarly to the method for making(S)-ethyl2-(3-(bromomethyl)-1-(4-chloro-phenyl)naphthalen-2-yl)-2-tert-butoxyacetateof Example 22. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₃H₃₇BrNO₄: 590.2.Found: 590.0, 592.0.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethylpivalate: To a solution of(S)-2-(3-(bromomethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)-2-tert-butoxyethylpivalate (15 mg, 0.0255 mmol) in acetonitrile (1 mL), was added AgF (8mg, 0.063 mmol). The reaction mixture was stirred at room temperaturefor 1 day. The reaction mixture was then washed by sat. NaHCO₃,extracted with EtOAc, dried over MgSO₄, filtered, concentrated in vacuoand purified by flash column chromatography (silica gel, 0 to 30% ethylacetate/hexanes) to provide 13 mg of the desired product. LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₃H₃₇FNO₄: 530.3. Found: 530.1.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethanol:To a solution of(S)-2-tert-butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethyl pivalate (13 mg, 0.024 mol) in THF (1 mL) and MeOH(0.5 mL), was added NaOH (2 N, 240 μL). The reaction mixture was reactedat room temperature for 1 day. The reaction mixture was washed with sat.NaHCO₃ and extracted with EtOAc. The organic layers were combined, driedover MgSO₄, concentrated and purified by flash column chromatography(silica gel, ethyl acetate/hexanes) to provide 5 mg of the desiredproduct. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₉FNO₃: 446.2. Found:446.0.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)aceticacid (31): To a solution of(2S)-2-tert-butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethanol(5 mg, 0.0112 mmol) in wet acetonitrile (0.75% wt H₂O) was addedH₅IO₆/CrO₃ (0.439 M stock solution in wet acetonitrile, 400 μL) at 0° C.The reaction mixture was stirred at 0° C. for 30 min. The reactionmixture was filtered and purified by reverse phase HPLC (Gemini, 5 to100% ACN/H₂O+0.1% TFA) to provide 0.8 mg of the desired product. ¹H-NMR:400 MHz, (CD₃OD) δ: 8.51 (d, J=2.4 Hz, 1H), 8.15 (s, 1H), 7.92 (d, J=4.0Hz, 1H), 7.69 (d, J=4.2 Hz, 1H), 7.54 (d, J=2.6 Hz, 1H), 7.43 (t, J=7.6Hz, 1H), 7.31 (d, J=4 Hz, 1H), 7.24-7.21 (m, 1H), 6.88 (d, J=4.4 Hz,1H), 6.01-5.74 (m, 2H), 5.06 (s, 1H), 4.59 (t, J=6.2 Hz, 2H), 3.49 (t,J=6 Hz, 2H), 0.81 (s, 9H). ¹⁹F-NMR 400 MHz (CD₃OD) δ: −77.51 (s, 1F).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇FNO₄: 460.2. Found: 460.1.

Example 30(S)-2-tert-Butoxy-2-((R)-3-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)aceticacid (32)

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-formylnaphthalen-2-yl)ethylpivalate: The compound was made similarly to (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-formylnaphthalen-2-yl)acetate ofExample 27. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₃H₃₆NO₅: 526.2. Found:526.1.

Preparation of(S)-2-tert-butoxy-2-((R)-3-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)ethylpivalate: To a solution of(S)-2-tert-butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-formylnaphthalen-2-yl)ethylpivalate (18 mg, 0.0343 mmol) in DCM (1.5 mL) was added Deoxofluor (20μL, 0.105 mmol). The reaction mixture was stirred at room temperatureovernight. More Deoxofluor (300 μL, 1.6 mmol) was added and the reactionmixture was stirred at room temperature over weekend. The reactionmixture was washed by sat. NaHCO₃ and extracted with DCM. The organiclayers were combined, concentrated in vacuo and purified by flash columnchromatography (silica gel, 0 to 30% ethyl acetate/hexanes) to produce20 mg of the desired product. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₃H₃₆F₂NO₄: 548.2. Found: 548.1.

Preparation of(S)-2-tert-butoxy-2-((R)-3-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)ethanol:The compound was made by the similar method to make(2S)-2-tert-butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)ethanolof Example 29. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₈F₂NO₃: 464.2.Found: 464.1.

Preparation of(S)-2-tert-butoxy-2-((R)-3-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)naphthalen-2-yl)aceticacid (32): The compound was made by the similar method to make(2S)-2-tert-butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-(fluoromethyl)naphthalen-2-yl)aceticacid of Example 29. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.66 (d, J=2.8 Hz, 1H),8.56 (s, 1H), 8.15 (d, J=4.2 Hz, 1H), 8.00-7.81 (m, 3H), 7.69-7.54 (m,2H), 7.45 (t, J=7.8 Hz, 1H), 7.04 (d, J=4.2 Hz, 1H), 5.10 (s, 1H), 4.75(t, J=6 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 1.07 (s, 9H). ¹⁹F-NMR 400 MHz(CD₃OD) δ: −77.77 (s, 2F). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₈H₂₆F₂NO₄: 478.1; Found: 478.1.

Example 31tert-Butoxy-[1-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]-aceticacid (33)

Preparation of 1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-ol: A mixtureof 2,4-dichlorophenylboronic acid (1.0 g),tetrakis(triphenylphosphine)palladium(0) (300 mg),1-bromo-3-methyl-naphthalen-2-ol (5B, 625 mg) in K₂CO₃ (2 M, 5.3 mL) andDME (26 mL) was degassed with argon and sealed in a Schlenk tube. Thereaction was heated to 80° C. for 75 minutes, then cooled to roomtemperature. The reaction was diluted with EtOAc and filtered through apad of silica gel. The silica was washed with EtOAc and the combinedorganics were concentrated. The crude residue was purified by flashcolumn chromatography (0-18% EtOAc in hexanes) to yield 784 mg ofdesired product.

Preparation of 1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yltrifluoromethanesulfonate:1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yl trifluoromethanesulfonatewas prepared in a similar manner as compound 4C in Example 2, exceptstarting from 1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-ol instead of4B. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.85-7.90 (m, 2H), 7.62 (d, 1H), 7.55(app dt, 1H), 7.41-7.48 (m, 2H), 7.32-7.49 (m, 2H), 2.64 (s, 3H).

Preparation oftert-butoxy-[1-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]-aceticacid (33):tert-butoxy-[1-(2,4-dichloro-phenyl)-3-methyl-naphthalen-2-yl]-aceticacid (33) was prepared in a similar manner as compound 3K in Example 1,except starting from 1-(2,4-dichlorophenyl)-3-methylnaphthalen-2-yltrifluoromethanesulfonate instead of 3E. ¹H-NMR: 400 MHz, (CD₃CN) δ:7.84 (d, 1H), 7.78 (s, 1H), 7.69 (d, 1H), 7.63 (d, 1H), 7.47-7.54 (m,2H), 7.37 (app dt, 1H), 7.16 (d, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.06(s, 9H).

Example 32tert-Butoxy-[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-aceticacid (34)

Preparation of 4-(2-methoxyphenyl)-3-methyl-but-2-enoic acid ethylester: In a 3-neck round bottom flask, fitted with an internalthermometer and addition funnel, a mixture of sodium hydride (60% inmineral oil, 4.14 g) in THF (200 mL), under argon, was cooled to 10° C.(Diethoxyphosphoryl)acetic acid ethyl ester (21 mL) was added dropwise(heat and gas evolution), keeping the internal temperature below roomtemperature. After addition, the reaction mixture was stirred at roomtemperature for minutes, and then cooled to 0° C. A solution of2-methoxyphenyl acetone (5 g) in THF (25 mL) was added dropwise over 5minutes. The reaction was allowed to warm to room temperature overnight.With active cooling, the reaction was quenched with H₂O (200 mL), thenAcOH (to pH ˜6) and extracted with EtOAc. The combined organics werewashed with NaHCO₃, water, and brine, dried over Na₂SO₄, andconcentrated. The crude residue was purified by flash columnchromatography to give the desired compound (5.73 g). ¹H-NMR: 400 MHz,(CDCl₃) δ: 7.24 (app dt, 1H), 7.10 (dd, 1H), 6.92 (d, 1H), 6.88 (d, 1H),5.58 (s, 1H), 4.13 (q, 2H), 3.82 (s, 3H), 3.46 (s, 2H), 1.26 (t, 3H).

Preparation of 4-(2-methoxyphenyl)-3-methyl-butyric acid ethyl ester:Palladium on carbon (10%, wet Degussa, 300 mg) was degassed. Ethanol (60mL), degassed with argon, was added followed by4-(2-methoxy-phenyl)-3-methyl-but-2-enoic acid ethyl ester (5.7 g, 24mmol). Hydrogen was bubbled through the ethanol, and the reaction wasstirred under 1 atm of H2 (balloon)overnight. The balloon was removed,and the reaction was flushed with argon and the reaction was filteredthrough Celite. The Celite was washed with ethyl acetate and thefiltrates dried over magnesium sulfate and concentrated. The cruderesidue was used without further purification. LCMS-ESI⁺ (m/z): [M]⁺calcd for C₁₄H₂₀O₃: 236.14. Found: 236.96.

Preparation of 4-(2-methoxyphenyl)-3-methyl-butyric acid: A solution of4-(2-methoxyphenyl)-3-methyl-butyric acid ethyl ester (24 mmol, crudefrom previous reaction) in THF (50 mL), EtOH (50 mL) and LiOH (1 M, 50mL) was stirred at room temperature overnight. The reaction wasacidified with 1 M HCl, and extracted with EtOAc. The combined extractswere washed with brine and dried over sodium sulfate. Concentration gavethe desired product, which was used without further purification.LCMS-ESI⁺ (m/z): [M]⁺ calcd for C₁₂H₁₆O₃: 208.11. Found: 208.86

Preparation of 4-(2-methoxyphenyl)-3-methyl-butyryl chloride: To asolution of 4-(2-methoxyphenyl)-3-methylbutyric acid (24 mmol, crudefrom previous reaction) in dichloromethane (36 mL) was added oxalylchloride (2 M in DCM, 36 mL). The reaction was stirred for 1 h at roomtemperature. All volatiles were removed in vacuo and the crude residueused without further purification.

Preparation of 5-methoxy-3-methyl-3,4-dihydro-2H-naphthalen-1-one: Amixture of AlCl₃ (6.4 g) and CH₂Cl₂ (100 mL) was cooled to 0° C. To themixture was added 4-(2-methoxyphenyl)-3-methylbutyryl chloride (24 mmol,crude from previous reaction). The reaction was allowed to warm slowlyto room temperature and then quenched by slowly pouring over ice. Themixture was extracted with dichloromethane (3×) and the combinedorganics were washed with 1 M HCl, water, dried over sodium sulfate, andconcentrated. Purification by flash column chromatography yielded thedesired product (1.65 g, 36% yield from4-(2-methoxy-phenyl)-3-methyl-but-2-enoic acid ethyl ester). LCMS-ESr(m/z): [M+H]⁺ calcd for C₁₂H₁₅O₂: 191.11. Found: 191.19.

Preparation of(5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-aceticacid ethyl ester: In a heavy walled sealed tube,5-methoxy-3-methyl-3,4-dihydro-2H-naphthalen-1-one (1.3 g, 6.8 mmol),ethyl glyoxylate (3 mL, 50% solution in toluene), benzenesulfonic acid(100 mg), magnesium sulfate (5 g), and toluene (30 mL) were heated to120° C. for 13 hours. The reaction was cooled to room temp, filtered,diluted with water, and extracted with ethyl acetate. The extracts werewashed with brine, dried with sodium sulfate, and concentrated. Thecrude residue was purified by flash column chromatography to yield thedesired product (960 mg, 51% yield). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₁₆H₁₉O₄: 275.13. Found: 275.26.

Preparation of(4-bromo-5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-aceticacid ethyl ester: A mixture of(5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-aceticacid ethyl ester (480 mg), NBS (420 mg), and AIBN (30 mg) in CCl₄ (18mL) was refluxed for 3 hours. The reaction mixture was then cooled toroom temperature, quenched with saturated sodium bicarbonate solutionand extracted with dichloromethane (2×). The combined organics werewashed with water, dried (Na₂SO₄), concentrated, and purified by flashcolumn chromatography to give a light brown solid (420 mg) LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₁₆H₁₈BrO₄: 353.03. Found: 352.91.

Preparation of(1-hydroxy-5-methoxy-3-methyl-naphthalen-2-yl)-(4-methoxy-benzyloxy)-aceticacid ethyl ester: To a solution of 4-methoxybenzyl alcohol (0.27 mL, 4equiv) in THF (11 mL) at 0° C. was added KHMDS (0.5 M in toluene, 3.4mL, 3 equiv) and the resulting mixture was allowed to stir for 10 min at0° C. A solution of(4-bromo-5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)-aceticacid ethyl ester (200 mg) in THF (1 mL) was added slowly. After stirringfor 3 min at 0° C., the reaction was quenched with citric acid (1 M) andextracted with EtOAc. The organic extracts were washed with brine, driedover Na₂SO₄ and concentrated. The crude residue was purified by flashcolumn chromatography (5-20% EtOAc/hexanes) to give 157 mg of paleorange oil (68% yield). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₄H₂₇O₆:411.18. Found: 411.21.

Preparation of(4-methoxybenzyloxy)-(5-methoxy-3-methyl-1-trifluoromethanesulfonyloxy-naphthalen-2-yl)-aceticacid ethyl ester: A solution of(1-hydroxy-5-methoxy-3-methyl-naphthalen-2-yl)-(4-methoxy-benzyloxy)-aceticacid ethyl ester (157 mg, 0.38 mmol) in dichloromethane (3.8 mL) wascooled to −78° C. under Ar. To the solution was added 2,6-lutidine (0.1mL) and triflic anhydride (0.1 mL) and stirred at −78° C. for 2.5 hours.Saturated sodium bicarbonate (3 mL) was added and the reaction mixturewas warmed to room temperature and diluted with dichloromethane. Thedichloromethane was separated, the aqueous layer extracted with CH₂Cl₂,and the combined organics dried over sodium sulfate and concentrated.The crude residue was purified by flash column chromatography to givethe desired product (128 mg, 62% yield). LCMS-ESI⁺ (m/z): [M+Na]⁺ calcdfor C₂₅H₂₅F₃NaO₈S: 565.11. Found: 565.23.

Preparation of[1-(4-chlorophenyl)-5-methoxy-3-methylnaphthalen-2-yl]-(4-methoxybenzyloxy)aceticacid ethyl ester: A solution of(4-methoxy-benzyloxy)-(5-methoxy-3-methyl-1-trifluoromethanesulfonyloxy-naphthalen-2-yl)-aceticacid ethyl ester (128 mg, 0.236 mmol), 4-chlorophenylboronic acid (74mg, 2 equiv), EtOH (0.5 mL), K₂CO₃ (2 M, 0.5 mL), and toluene (1.3 mL)were degassed with argon at room temperature in a Schlenk tube.Pd(dppf)Cl₂ was then added (17 mg) and the tube sealed. The reaction washeated to 60° C. for 14 hours. Analysis of the reaction mixture by LCMSshowed 40% conversion, with visual analysis showing significant amountof palladium black. The crude mixture was filtered via syringe through amicrofilter into a new sealable tube charged with Pd(PPh₃)₄. The tubewas sealed and heated to 100° C. for 16 hours. The reaction was cooledto room temperature, diluted with EtOAc and filtered through Celite. Thefiltrate was concentrated, and the crude residue purified by flashcolumn chromatography to give the desired product (60 mg, 50% yield).LCMS-ESI⁺ (m/z): [M+Na]⁺ calcd for C₃₀H₂₉ClNaO₅: 527.99. Found: 527.44.

Preparation of[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-hydroxy-aceticacid ethyl ester: To a solution of[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-(4-methoxy-benzyloxy)-aceticacid ethyl ester (58 mg, 0.115 mmol) in dichloromethane (3 mL) was addedtrifluoroacetic acid (58 L). The reaction mixture was stirred for 2 h atroom temperature and then quenched carefully with sat. NaHCO₃. Theaqueous layer was extracted with dichloromethane twice, and then thecombined organic layers were washed with water, dried (Na₂SO₄),concentrated and purified by flash column chromatography to give desired(23 mg).

Preparation oftert-butoxy-[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-aceticacid ethyl ester: A solution of[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-hydroxy-aceticacid ethyl ester (23 mg) and perchloric acid, 70% (3 μL) in tert-butylacetate (1 mL) was stirred at room temperature for 2 h. After 2 h, thereaction had apparently stalled, so 3 μL additional perchloric acid wasadded. After 2 additional hours, no further conversion was observed(LCMS analysis). Saturated sodium bicarbonate solution was added and themixture was extracted with ethyl acetate (3×). The combined organiclayer was dried (Na₂SO₄), and concentrated. The crude mixture waspurified by flash column chromatography to givetert-butoxy-[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-aceticacid ethyl ester (9 mg) plus 7 mg of recovered starting material. Therecovered starting material was re-subjected to similar reactionconditions to yield an additional 3 mg of desired. ¹H-NMR: 400 MHz,(CDCl₃) δ: 8.10 (s, 1H), 7.39-7.48 (m, 3H), 7.25 (s, 1H), 7.17 (app t,1H), 6.78 (app t, 2H), 5.09 (s, 1H), 4.06-4.20 (m, 2H), 3.99 (s, 3H),2.61 (s, 3H), 1.185 (t, 3H), 0.98 (s, 9H).

Preparation oftert-butoxy-[1-(4-chlorophenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-aceticacid (34): To a solution oftert-butoxy-[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-aceticacid ethyl ester (12 mg) in THF (0.3 mL) and EtOH (0.1 mL) was added 0.1mL of 1 M LiOH. The reaction was stirred for 30 min at room temperature,then 0.3 mL each of THF, EtOH, and 1 M NaOH were added. The reaction washeated to 70° C. for 2.5 hours, and then cooled to room temperature.Formic acid was added until pH ˜5. The reaction mixture was directlypurified by HPLC (Gemini, 50-100% MeCN/H₂O, with 0.1% TFA). The productwas lyophilized to give a white powder (8 mg).

¹H-NMR: 400 MHz, (CD₃CN) δ: 8.09 (s, 1H), 7.49-7.58 (m, 3H), 7.32 (br d,1H), 7.26 (app t, 1H), 6.91 (d, 1H), 6.81 (d, 1H), 5.19 (s, 1H), 3.99(s, 3H), 2.57 (s, 3H), 0.99 (s, 9H). LCMS-ESI⁺ (m/z): [M-OtBu]⁺ calcdfor C₂₀H₁₆ClO₃: 339.79. Found: 339.07.

Example 33 Ethyl 2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (35)

Preparation of ethyl2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate(35): Ethyl2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate (35) was prepared similarly to ethyl2-(6-methoxy-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetateof Example 32, using 1-(2-bromophenyl)propan-2-one as the startingmaterial instead of 1-(3-methoxyphenyl)propan-2-one. ¹H-NMR: 400 MHz,(CDCl₃) δ: 8.11 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H),7.40 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 2H), 6.81 (d, J=7.6 Hz, 2H),5.61 (s, 1H), 4.62 (q, J=11.2 Hz, 2H), 4.26-4.15 (m, 2H), 3.75 (s, 3H),2.62 (s, 3H), 1.18 (t, J=6.8 Hz, 3H).

Example 34 Ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate(36A) and Ethyl2-(1,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (36B):

Preparation of ethyl 2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate: Prepared similarly to ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetateof Example 67, using ethyl2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetateinstead of ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate.¹H-NMR: 400 MHz, (CDCl₃) δ: 8.20 (s, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.95(dd, J=7.4, 0.8 Hz, 1H), 7.48 (t, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H),2.54 (s, 3H), 1.40 t, J=7.6 Hz, 3H).

Preparation of ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate(36A) and ethyl2-(1,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (36B):To a solution of ethyl2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate(1.2 g, 2.56 mmol) and 4-chlorophenylboronic acid (440 mg, 2.81 mmol) intoluene was added 2 M potassium carbonate (2.8 mL, 5.63 mmol) andPdCl₂(dppf) (187 mg, 0.256 mmol) and the reaction was degassed withargon 10 minutes. The reaction was stirred at room temperature for 4hours. The reaction was filtered, diluted with water, extracted withethyl acetate and concentrated. The crude reaction was purified by flashcolumn chromatography (silica gel, ethyl acetate/hexanes) followed byreverse phase HPLC (Gemini, 40-100% ACN/H₂O+0.1% TFA). Product waslyophilized to give 670 mg of ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate(36A) as a yellow oil, ¹H-NMR: 400 MHz, (CDCl₃) δ: 8.20 (s, 1H), 8.13(d, J=8.8 Hz, 1H), 7.85 (d, J=6.8 Hz, 1H), 7.68 (t, J=7.2 Hz, 1H), 7.51(d, J=8.8 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 3.95 (q, J=6.8 Hz, 2H), 2.41(s, 3H), 1.14 (t, J=7.2 Hz, 5H); and 109 mg of ethyl2-(1,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (36B)as a white solid. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.72 (s, 1H), 7.59-7.56(m, 1H), 7.50 (t, J=8.0 Hz, 2H), 7.46-7.44 (m, 5H), 7.43 (d, J=2.4 Hz,1H), 7.28 (d, J=8.0 Hz, 2H), 3.94 (q, J=7.2 Hz, 2H), 2.42 (s, 3H), 1.14(t, J=7.2 Hz, 3H).

Example 352-(5-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (37)

Preparation of ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate:Prepared similarly to ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateof Example 67 using ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetateinstead of ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate.Product was carried on crude to next reaction.

Preparation of2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (37): To a solution of ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(30 mg, 0.061 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 3 mL) wasadded lithium hydroxide (7 mg, 0.31 mmol) and the reaction was heated to50° C. overnight. Crude reaction purified by reverse phase HPLC (Gemini,40-100% ACN/H₂O+0.1% TFA). Product lyophilized to give a white powder(5.9 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.07 (s, 1H), 7.77 (d, J=6.0 Hz,1H), 7.58 (s, 2H), 7.55 (as, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.8Hz, 1H), 7.18 (m, 1H), 5.17 (s, 1H), 2.67 (s, 3H), 0.99 (s, 9H).LCMS-ESF (m/z): [M−H]⁻ calcd for C₂₃H₂₁BrClO₃: 460.8. found; 460.2.

Example 362-(1,5-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (38)

Preparation of2-(1,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (38):2-(1,5-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (38) was prepared similarly to2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid of Example 35 using ethyl2-(1,5-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate insteadof ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate.¹H-NMR: 400 MHz, (CD₃OD) δ: 7.59 (m, 4H), 7.53 (d, J=8.4 Hz, 2H), 7.45(d, J=8.4 Hz, 2H), 7.35 (m, 3H), 7.28 (m, 1H), 5.18 (s, 1H), 2.51 (s,3H), 0.99 (s, 9H). LCMS-ESF (m/z): [M−H]⁻ calcd for C₂₉H₂₆Cl₂O₃: 491.13.found: 491.42.

Example 372-tert-Butoxy-2-(1-(4-chlorophenyl)-5-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (39)

Preparation of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-5-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)acetate:To a solution of ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(100 mg, 0.20 mmol) and N,N-dimethylprop-2-yn-1-amine (0.065 mL, 0.61mmol) in anhydrous tetrahydrofuran was added copper iodide (8 mg, 0.04mmol) and PdC12(PPh₃)₂ (14 mg, 0.02 mmol). The reaction was heated to100° C. overnight. After cooling to room temperature the reaction wascharged with PdC12(PPh₃)₂ (14 mg, 0.02 mmol), copper iodide (8 mg, 0.04mmol), N,N-dimethylprop-2-yn-1-amine (0.065 mL, 0.61 mmol) andtriethylamine (1 mL). The reaction was heated to 100° C. overnight. Tothe reaction was then added N,N-dimethylprop-2-yn-1-amine (0.065 mL,0.61 mmol) and heated to 100° C. overnight. The crude reaction mixturewas absorbed onto silica gel and purified by flash column chromatography(silica gel, ethyl acetate/hexanes, methanol/ethyl acetate) to give ayellow oil (6.5 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₅ClNO₃:492.22. found: 492.15.

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-5-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (39): To a solution of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-5-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)acetate(6.5 mg, 0.013 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 4 mL) wasadded lithium hydroxide (2 mg, 0.066 mmol) and the reaction was heatedto 50° C. overnight. The reaction was purified by reverse phase HPLC(Gemini, 40-60% ACN/H₂O+0.1% TFA). The product was lyophilized to give awhite powder (1.2 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.14 (s, 1H), 7.74(d, J=6.4 Hz, 1H), 7.58 (s, 2H), 7.56 (as, 1H), 7.33 (m, 3H), 5.18 (s,1H), 4.42 (s, 2H), 3.04 (s, 6H), 2.67 (s, 3H), 0.99 (s, 9H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₈H₃₁ClNO₃: 464.19. found: 464.51.

Example 382-tert-Butoxy-2-(1-(4-chlorophenyl)-3,5-dimethylnaphthalen-2-yl)aceticacid (40)

Preparation of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3,5-dimethylnaphthalen-2-yl)acetate:To a solution of ethyl2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(100 mg, 0.204 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane(0.086 mL, 0.61 mmol) in toluene:ethanol (2:1, 3 mL) and water (1 mL)was added potassium carbonate (282 mg, 2.04 mmol) and PdCl₂(dppf) (15mg, 0.02 mmol) and the reaction was degassed with argon for 10 minutes.The reaction was heated to 100° C. for 20 minutes in a microwavereactor. The crude reaction was purified by flash column chromatography(silica gel, ethyl acetate/hexanes) to give a yellow oil (32 mg) ¹H-NMR:400 MHz, (CD₃OD) δ: 8.08-7.87 (m, 2H), 7.87 (s, 1H), 7.65-7.35 (m, 1H),7.26 (m, 2H), 7.15 (d, J=7.2 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H). 5.10 (s,1H), 4.14 (m, 2H), 2.69 (s, 3H), 2.65 (s, 3H), 1.20 (t, J=6.8 Hz, 3H),0.99 (s, 9H).

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3,5-dimethylnaphthalen-2-yl)aceticacid (40): To a solution of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3,5-dimethylnaphthalen-2-yl)acetate(32 mg, 0.075 mmol) in tetrahydrofuran: ethanol:water (2:2:1, 3 mL) wasadded lithium hydroxide (9 mg, 0.377 mmol) and the reaction was heatedto 50° C. overnight. The reaction was purified by reverse phase HPLC(Gemini, 40-100% ACN/H₂O+0.1% TFA). The product was lyophilized to givea white powder (16.8 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.86 (s, 1H), 7.54(m, 3H), 7.29 (m, 2H), 7.16 (t, J=8.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H),5.17 (s, 1H), 2.69 (s, 3H), 2.65 (s, 3H), 0.98 (s, 9H). LCMS-ESI⁻ (m/z):[M−H]⁻ calcd for C₂₄H₂₄ClO₃: 395.15. found: 394.97.

Example 392-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (41)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (41):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (41) was prepared similarly to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,5-dimethylnaphthalen-2-yl)aceticacid of Example 38 using pyrimidin-5-ylboronic acid in place of2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. ¹H-NMR: 400 MHz, (CD₃OD)δ: 9.27 (s, 1H), 8.95 (s, 2H), 7.60 (s, 2H), 7.58 (s, 1H), 7.54 (s, 1H),7.43 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 5.20 (s, 1H), 2.55 (s, 3H), 1.00(s, 9H). LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₇H₂₆ClN₂O₃: 461.16. found:461.45.

Example 402-tert-Butoxy-2-(1-(4-chlorophenyl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid (42

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid (42):2-tert-Butoxy-2-(1-(4-chlorophenyl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid (42) was prepared similarly to2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid of Example 35, using6-fluoro-3-methyl-3,4-dihydronaphthalen-1(2H)-one instead of5-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one. ¹H-NMR: 400 MHz,(CD₃OD) δ: 7.67 (s, 1H), 7.57 (s, 2H), 7.55 (as, 1H), 7.45 (dd, J=9.8,2.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.27 (dd, J=9.4, 5.2 Hz, 1H), 7.11(td, J=9.0, 2.4 Hz, 1H) 5.16 (s, 1H), 2.60 (s, 3H), 0.98 (s, 9H).¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −118.01 (s). LCMS-ESF (m/z): [M—H]⁻ calcdfor C₂₃H₂₁ClFO₃: 399.12. found: 399.19.

Example 412-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid (43)

Preparation of2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid (43):2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid (43) was prepared similarly to2-tert-butoxy-2-(1-(4-chlorophenyl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 40 using 1-(3-fluorophenyl)propan-2-one instead of1-(2-bromophenyl)propan-2-one and2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid instead of4-chlorophenylboronic acid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.67 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.75 (d, J=5.2 Hz, 1H),7.59 (dd, J=9.6, 2.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.07 (td, J=9.2,2.8 Hz, 1H), 6.98 (m, 1H), 5.21 (s, 1H), 4.71 (m, 2H), 3.64 (t, J=6.0Hz, 2H), 2.77 (s, 3H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ:−116.92 (s). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇FNO₄: 460.18.found: 460.15.

Example 422-tert-Butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (44)

Preparation of2-tert-butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (44):2-tert-Butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (44) was prepared similarly to2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid (43) using 1-(2-fluorophenyl)propan-2-one instead of1-(3-fluorophenyl)propan-2-one. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.68 (d,J=5.6 Hz, 1H), 8.56 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 7.78 (d, J=5.6 Hz,1H), 7.43 m, 1H), 7.19 (m, 2H), 6.73 (M, 1H), 5.23 (s, 1H), 4.67 (m,2H), 3.57 (t, J=5.6 Hz, 2H), 2.75 (s, 3H), 0.85 (s, 9H). ¹⁹F-NMR: 377MHz, (CD₃OD) δ: −125.97 (t, J=7.54 Hz). LCMS-ESI⁻ (m/z): [M−H]⁻ calcdfor C₂₈H₂₇FNO₄: 458.18. found: 457.76.

Example 432-tert-Butoxy-2-(5-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (45)

Preparation of2-tert-butoxy-2-(5-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (45):2-tert-Butoxy-2-(5-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (45) was prepared similarly to2-tert-butoxy-2-(1-(4-chlorophenyl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 40 using 1-(2-chlorophenyl)propan-2-one instead of1-(3-fluorophenyl)propan-2-one. ¹H-NMR: 400 MHz, (CDCl₃) δ: 8.14 (s,1H), 7.64 (m, 1H), 7.54 (m, 2H), 7.50 (d, J=7.6 Hz, 1H), 7.23 (m, 3H),5.27 (s, 1H), 2.64 (s, 3H), 1.03 (s, 9H). LCMS-ESI (m/z): [M−H]⁻ calcdfor C₂₃H₂₁Cl₂O₃: 415.09. found; 415.09.

Example 442-tert-Butoxy-2-(1-(4-chlorophenyl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (46)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (46):2-tert-Butoxy-2-(1-(4-chlorophenyl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (46) was prepared similarly to2-tert-butoxy-2-(1-(4-chlorophenyl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 40 using 1-(2-fluorophenyl)propan-2-one instead of1-(3-fluorophenyl)propan-2-one. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.94 (s,1H), 7.59 (s, 2H), 7.57 (m, 1H), 7.35 (d, J=8.8 Hz, 1 h), 7.27 (m, 1 h),7.16 (m, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.21 (s, 1H), 2.66 (s, 3H), 1.01(s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −126.85 (dd, J=10.2, 5.3 Hz).LCMS-ESI-(m/z): [M−H]⁻ calcd for C₂₃H₂₁ClFO₃: 399.12. found: 399.14.

Example 452-tert-Butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (47)

Preparation of2-tert-butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (47):2-tert-Butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (47) was prepared similarly to2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 41 using 1-(2-chlorophenyl)propan-2-one instead of1-(3-fluorophenyl)propan-2-one. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.65 (d,J=5.2 Hz, 1H), 8.33 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.69 (d, J=5.2 Hz,1H), 7.60 (d, J=7.6 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.19 (t, J=8.4 Hz,1H), 6.91 (d, J=8.4 Hz, 1H), 5.24 (s, 1H), 4.70 (m, 2H), 3.61 (t, J=6.0Hz, 2H), 2.82 (s, 3H), 0.93 (s, 9H). LCMS-ESI⁻ (m/z): [M−H]⁻ calcd forC₂₈H₂₅ClNO₄: 474.16. found: 474.08.

Example 462-tert-Butoxy-2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)aceticacid (48)

Preparation of ethyl2-(6-methoxy-3-methyl-1-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate:Ethyl2-(6-methoxy-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetatewas prepared similarly as the preparation of ethyl2-(5-methoxy-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetateof Example 32 using 6-methoxy-3-methyl-3,4-dihydronaphthalen-1(2H)-oneinstead of 5-methoxy-3-methyl-3,4-dihydronaphthalen-1(2H)-one. ¹H-NMR:400 MHz, (CDCl₃) δ: 7.93 (d, J=9.2 Hz, 1H), 7.56 (s, 1H), 7.25-7.21 (m,3H), 7.07 (d, J=2.4 1H), 6.82 (d, J=8.8 Hz, 2H), 5.57 (s, 1H), 4.62-4.55(m, 2H), 4.27-4.13 (m, 2H), 3.93 (s, 3H), 3.77 (s, 3H), 2.53 (s, 3H),1.18 (t, J=6.8 Hz, 3H).

Preparation of ethyl2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate:To a solution of ethyl2-(6-methoxy-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyl-oxy)acetate(100 mg, 0.184 mmol) and 4-chlorophenylboronic acid (58 mg, 0.37 mmol)in 1,2-dimethoxyethane (2 mL) was added 2 M potassium carbonate (0.368mL, 0.74 mmol) and Pd(PPh₃)₄ (21 mg, 0.018 mmol) and the reaction wasdegassed for 15 minutes with argon. The mixture was heated to 120° C.for 20 minutes in a microwave reactor. The crude reaction was absorbedonto silica and purified by flash column chromatography (silica gel,ethyl acetate/hexanes) to produce a yellow oil (66 mg). ¹H-NMR: 400 MHz,(CDCl₃) δ: 7.58 (s, 1H), 7.39 (dd, J=8.2, 1.6 Hz, 1H), 7.31-7.26 (m,2H), 7.13-7.07 (m, 4H), 7.01 (dd, J=8.2, 2.4 Hz, 1H), 6.94 (dd, J=9.2,2.8 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.77 (m, 1H), 4.50 (s, 1H), 4.42(ABd, J=11.2 Hz, 1H), 4.34 (ABd, J=11.2 Hz, 1H), 4.20-4.15 (m, 2H), 3.91(s, 3H), 3.81 (s, 3H), 2.60 (s, 3H), 1.21 (t, J=7.2 Hz, 3H).

Preparation of ethyl2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)-2-hydroxyacetateand ethyl2-(1-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate:To a solution of ethyl2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate(185 mg, 0.37 mmol) in dichloromethane at 0° C. was addedtrifluoroacetic acid (0.185 mL, 2.4 mmol) and the reaction was allowedto warm to room temperature over 2 hours. The reaction was quenched withsaturated sodium bicarbonate with active cooling, extracted withdichloromethane and concentrated. The crude reaction was purified byflash column chromatography (silica gel, ethyl acetate/hexanes) and thenfurther purified by reverse phase HPLC (Gemini, 20-100% ACN/H₂O+0.1%TFA) to give the two products: ethyl2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate:27 mg clear oil. LCMS-ESI⁺ (m/z): [M+H—H₂O]⁺ calcd for C₂₂H₁₉ClO₃:367.09. found: 367.05: and ethyl2-(1-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate:105 mg as a brown oil. LCMS-ESI⁺ (m/z): [M+H—H₂O]⁺ calcd for C₃₀H₂₇ClO₄:487.15. found: 486.90.

Preparation of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)acetate:To a solution of ethyl2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate(27 mg, 0.07 mmol) in tert-butylacetate (1.0 mL) was added 70%perchloric acid (0.012 mL, 0.14 mmol) and the reaction was stirred atroom temperature for 1.5 hours. The reaction was quenched with solidsodium bicarbonate, water (2 mL) added and stirred 1 hour. The productwas extracted with ethyl acetate, concentrated and purified by flashcolumn chromatography (silica gel, ethyl acetate/hexanes) to give acolorless oil (16.2 mg). ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.48 (s, 1H),7.41-7.36 (m, 3H), 7.19 (d, J=6.4 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 6.99(br s, 1H), 6.86 (d, J=9.2 Hz, 1H), 5.00 (s, 1H), 4.12-4.02 (m, 2H),3.82 (s, 3H), 2.52 (s, 3H), 1.13 (t, J=7.2 Hz, 3H), 0.91 (s, 9H).

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)aceticacid (48): To a solution of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)acetate(16.2 mg, 0.037 mmol) in tetrahydrofuran:ethanol:water (2:2:1, 2.5 mL)was added lithium hydroxide (4 mg, 0.183 mmol) and the reaction washeated at 50° C. overnight. The reaction was purified by reverse phaseHPLC (Gemini, 20-90% ACN/H₂O+0.1% TFA) to give a white powder (12 mg).¹H-NMR: 400 MHz, (CD₃OD) δ: 7.60 (s, 1H), 7.55 (m, 3H), 7.30 (m, 1H),7.17 (d, J=2.8 Hz, 1H), 7.13 (d, J=9.6 Hz, 1H), 6.94 (dd, J=9.2, 2.8 Hz,1H), 5.15 (s, 1H), 3.90 (s, 3H), 2.58 (s, 3H), 0.98 (s, 9H). LCMS-ESF(m/z): [M−H]⁻ calcd for C₂₄H₂₄ClO₄: 411.14. found: 411.14.

Example 472-tert-Butoxy-2-(1-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3-methylnaphthalen-2-yl)aceticacid (49)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3-methylnaphthalen-2-yl)aceticacid (49):2-tert-Butoxy-2-(1-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3-methylnaphthalen-2-yl)aceticacid (49) was prepared following the procedure for2-tert-butoxy-2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)aceticacid of Example 46 using ethyl2-(1-(4-chlorophenyl)-6-methoxy-5-(4-methoxybenzyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetatein place of ethyl2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate.¹H-NMR: 400 MHz, (CD₃OD) δ: 7.75 (s, 1H), 7.54 (m, 3H), 7.32 (d, J=6.8Hz, 1H), 7.22 (m, 2H), 7.07 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H),5.12 (s, 1H), 4.38 (s, 2H), 3.90 (s, 3H), 3.72 (s, 3H), 2.52 (s, 3H),0.97 (s, 9H). LCMS-ESI⁻ (m/z): [M−H]⁻ calcd for C₃₂H₃₂ClO₅: 531.20.found: 531.01.

Example 48 6-Bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one (50)

Preparation of 6-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one (50): Aflask was charged with trifluoromethane sulfonic acid (450 g, 3 mol) andcooled to 0° C. with an ice-water bath.4-(3-bromophenyl)-3-methylbutanoic acid, prepared in a similar manner asdescribed in Example 32 (15.5 g, 60 mmol), was added as a solution inDCM (30 mL) slowly to produce a clear dark brown solution. After 15 min,the reaction was diluted with 500 mL of CHCl₃ and poured slowly ontoapproximately 1 L of crushed ice. The resulting slurry was allowed tostir until the solution warms to room temperature and became biphasic.Following separation of layers, the aqueous layer was extracted withCHCl₃. The combined organics were washed with brine and dried overanhydrous MgSO₄ prior to concentration in vacuo. Purification via Iscocolumn chromatography (50% DCM/hex isocratic) provided a quantitativeyield of the named compound as a pale yellow amorphous solid. LCMS-ESI⁺(m/z): [M]⁺ calcd for C₁₁H₁₁BrO: 239.11. found: 239.20.

Example 49 7-Bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one (51)

Preparation of 7-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one (51): Asolution of 4-(4-bromophenyl)-3-methylbutanoic acid, prepared in asimilar manner as described in Example 32 (6.43 g, 25.0 mmol), in H₂SO₄(25 mL) was stirred at 75° C. for 3 h. The mixture was slowly pouredonto ice. The resulting slurry was extracted with EtOAc (2×100 mL). Thecombined organic layers were washed with brine, dried, filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (EtOAc/hexanes) to give 5.74 g (96%) of the titlecompound. ¹H-NMR: 400 MHz, (CDCl₃) δ: 8.10 (d, J=2 Hz, 1H), 7.54 (dd,J=8, 2 Hz, 1H), 7.11 (d, J=8 Hz, 1H), 2.91 (d, J=16 Hz), 2.71 (d, J=13Hz), 2.58 (m, 1H), 2.28 (m, 2H), 1.12 (d, J=6 Hz, 3H).

Example 50(6-Bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2yloxy)triisopropylsilane(52)

Preparation of(6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-yloxy)triisopropylsilane(52)

Step 1: Preparation of 6-methoxy-3-methyl-3,4-dihydronaphthalen-1-yltrifluoromethanesulfonate: To a solution of6-methoxy-3-methyl-3,4-dihydronaphthalen-1(2H)-one (10.06 g, 53 mmol;prepared similarly to 6-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one(50) of Example 48 beginning with 1-(3-methoxyphenyl)propan-2-one),cooled to 0° C. was added 2,6-di-tert-butyl-4-methylpyridine (19.6 g,95.4 mmol) followed by trifluoromethanesulfonic anhydride (13.3 mL, 79.4mmol). The resulting solution was allowed to warm slowly to roomtemperature over 1.5 h and then quenched by addition of 1 M HCl (100mL). Following separation, the aqueous layer was extracted with DCM(3×100 mL) and the combined organics washed with brine. Followingconcentration in vacuo, the residue was taken up in hexanes. Theresulting precipitated solids were removed via filtration and the motherliquor was dried over anhydrous MgSO₄ and then concentrated in vacuo.The resulting residue was purified by Yamazen column chromatography (3%to 35% EtOAc/Hex) to produce 9.88 g (57%) of the title compound as acolorless syrup. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.28 (s, 1H); 6.75 (m, 2H);5.74 (d, J=4 Hz, 1H); 3.82 (s, 3H); 2.77 (m, 1H) 2.89 (dd, J=15.2, 10Hz; 1H); 2.61 (dd, J=15.2, 10 Hz; 1H); 1.14 (d, J=7.2 Hz, 3H).

Step 2: Preparation of4-(4-chlorophenyl)-7-methoxy-2-methyl-1,2-dihydronaphthalene:6-methoxy-3-methyl-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate(9.88 g, 30.7 mmol), 4-chlorophenylboronic acid (6.23 g, 39.9 mmol) andK₂CO₃ (12.7 g, 91.9 mmol) were combined in a mixture oftoluene/ethanol/water (80 mL/40 mL/40 mL) at room temperature in a heavywalled pressure flask. Following sparging of the mixture with Ar for 30minutes, PdCl₂(dppf) (1.12 g, 1.53 mmol) was added in one portion andthe flask was sealed and heated to 50° C. for 2.5 h. After returning toroom temperature, the layers were separated and the aqueous layer wasextracted with EtOAc and Hex (2×50 mL each). The combined organics werewashed with brine, filtered through a pad of Celite, and dried overanhydrous MgSO₄. The resulting solution was absorbed on silica gel invacuo and purified via Yamazen column chromatography (0-15% EtOAc/Hex)to provide 7.7 g (88%) of the title compound as an amorphous whitesolid. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.32 (d, J=8 Hz, 2H); 7.26 (d, J=8Hz, 2H); 6.87 (d, J=8.4 Hz, 1H); 6.57 (d, J=2.8 Hz, 1H); 6.62 (dd,J=8.4, 2.8 Hz, 1H); 5.74 (d, J=2.8 Hz, 1H); 3.79 (s, 3H); 2.81 (ABq,J=20.8, 12.4 Hz, 1H); 2.60 (m, 1H); 2.59 (ABq, J=8.4, 2.8 Hz, 1H); 1.14(d, J=6.4 Hz, 3H).

Step 3: Preparation of3-bromo-4-(4-chlorophenyl)-7-methoxy-2-methyl-1,2-dihydronaphthalene: Asolution of 4-(4-chlorophenyl)-7-methoxy-2-methyl-1,2-dihydronaphthalene(5 g, 17.6 mmol) in DCM (120 mL) was cooled in an ice-water bath priorto addition of solid pyridinium perbromide (6.2 g, 19.3 mmol) in oneportion. The dark blue solution was allowed to stir for 30 min and wasquenched by addition of saturated Na₂S₂O₃ (200 mL). The reaction wasfurther diluted with water and DCM before separation and extraction ofthe aqueous layer with DCM. The combined pink organics were washed withbrine and dried over anhydrous MgSO₄. Following filtration andconcentration in vacuo, the resulting residue was purified by Yamazencolumn chromatography (0-10% EtOAc/Hex) to afford 5.5 g (86%) of thetitle compound as an orange colored gel. LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₁₈H₁₇BrClO: 364.68; found: 364.89.

Step 4: Preparation of2-bromo-1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalene: A solution of3-bromo-4-(4-chlorophenyl)-7-methoxy-2-methyl-1,2-dihydronaphthalene(5.5 g, 15.1 mmol) in toluene (100 mL) was vacuum flushed with Ar. DDQ(5.2 g, 22.7 mmol) was added and the mixture heated to reflux for 1.5 h.The heterogeneous red-brown mixture was cooled to room temperature andthe toluene removed in vacuo. The resulting residue was taken up in DCM(300 mL) and filtered to remove precipitated DDHQ. The resulting motherliquor was absorbed on silica gel and purified by Yamazen columnchromatography (15% DCM/Hex) to afford 5.21 g (95%) of the titlecompound as an amorphous yellow solid. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.66(s, 1H); 7.49 (br d, J=2 Hz, 2H); 7.24-7.18 (m, 3H); 7.07 (d, J=2 Hz,1H); 6.97 (dd, J=9.2, 2 Hz, 1H); 3.91 (s, 3H); 2.60 (s, 3H).

Step 5: Preparation of6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-ol: A vessel was chargedwith boron tribromide (1 M in DCM, 0.7 mL, 0.7 mmol) and cooled to −78°C. 2-bromo-1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalene (0.1 g, 0.28mmol) was added as a solution in DCM (0.5 mL). The reaction was allowedto slowly warm to room temperature over 3.5 h. This procedure wasrepeated twice on a scale of 1 g and 4.1 g of2-bromo-1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalene withappropriate adjustments in the scale of other reagents. The three lotswere combined, cooled to 0° C. and the volume of the reaction was slowlydoubled with MeOH. After warming to room temperature, the mixture wasconcentrated in vacuo and the residue was taken up in EtOAc (150 mL),treated with saturated NaHCO₃ (150 mL) and then small portions of solidNaHCO₃ until the solution was pH ˜7. The layers were separated and theaqueous layer was extracted with EtOAc. The combined organics werewashed with brine, dried over anhydrous MgSO₄, and concentrated invacuo. The resulting residue was purified by Yamazen columnchromatography (5-25% EtOAc/Hex) to afford 4.54 g (91%) of the titlecompound as a colorless syrup. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₁₇H₁₃BrClO: 348.64. found: 348.79.

Step 6: Preparation of(6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-yloxy)triisopropylsilane(52): 6-Bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-ol (4.5 g, 12.9mmol) was taken up in DCM (65 mL). Added to this solution were TIPSCl(4.1 mL, 19.4 mmol), DBU (3.5 mL, 23.2 mmol), and DMAP (0.16 g, 1.3mmol). After stirring at room temperature overnight, the DCM was removedin vacuo and the residue taken up in hexane (200 mL). This solution waswashed with 1 M HCl (100 mL) and the layers separated. Followingextraction of the aqueous layer with hexanes, the combined organics werewashed with brine, dried over anhydrous MgSO₄ and concentrated in vacuo.The resulting residue was purified by Yamazen column chromatography(2-5% DCM/Hex) to afford 5.12 g (79%) of the title compound as acolorless syrup. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.61 (s, 1H); 7.49 (br d,J=8.4 Hz, 2H); 7.23 (br d, J=8.4 Hz, 2H); 7.17 (d, J=8.8 Hz, 1H), 7.16(d, J=2.4 Hz, 1H); 6.95 (dd, J=8.8, 2.4 Hz; 1H); 2.60 (s, 3H); 1.30(hep, J=7.2 Hz, 3H); 1.12 (d, J=7.2 Hz, 18H).

Example 51(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-4-yl)naphthalen-2-yl)aceticacid (53)

Step 1: Preparation of ethyl2-(1-(4-chlorophenyl)-3-methyl-6-(triisopropyl-silyloxy)naphthalen-2-yl)-2-oxoacetate:To a solution of(6-bromo-5-(4-chlorophenyl)-7-methylnaphthalen-2-yloxy)triisopropylsilane(2.5 g, 4.9 mmol) in THF (50 mL) cooled to −78° C. was added n-BuLi (1.6M in hexanes, 4.6 mL, 7.4 mmol) dropwise. The resulting solution wasallowed to stir at −78° C. for 30 min before addition of diethyl oxalate(1.7 mL, 12.4 mmol). After 45 min at −78° C., the cold bath was removedand the reaction allowed to warm to room temperature over 1 h. 5% citricacid (50 mL) solution was added and the layers separated. Followingextraction with EtOAc, the combined organics were washed with brine,dried over anhydrous MgSO₄ and concentrated in vacuo. The resultingresidue was purified by Yamazen column chromatography (0-10% EtOAc/Hex)to afford 2.10 g (81%) of the title compound as a colorless syrup.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₈ClO₄Si: 526.16. found: 526.89.

Step 2: Preparation of ethyl2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate:To a solution of ethyl2-(1-(4-chlorophenyl)-3-methyl-6-(triisopropylsilyloxy)naphthalen-2-yl)-2-oxoacetate(5.11 g, 9.7 mmol) in THF (25 mL) cooled to 0° C. was added TBAF (1 M inTHF, 10.7 mL, 10.7 mmol). After 15 min, a solution ofN-Phenyl-bis(trifluoromethane-sulfonimide) (5.2 g, 14.6 mmol) in THF (20mL) was added to produce a clear yellow solution. Solid potassiumcarbonate (2.7 g, 19.4 mmol) was added and the cold bath removed. After4 h at room temperature, the reaction was diluted with EtOAc and 1 MNaOH (100 mL each) and shaken vigorously for 5 min. The layers wereseparated and the aqueous extracted with EtOAc. The combined organicswere washed with brine, dried over anhydrous MgSO₄ and concentrated invacuo. The resulting residue was purified by Yamazen columnchromatography (0-20% EtOAc/Hex) to produce 3.12 g (64%) as an amorphouspale yellow solid. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.80 (s, 1H); 7.76 (d,J=2.4 Hz, 1H); 7.67 (d, J=9.6 Hz, 1H); 7.48 (br d, J=8.4 Hz, 2H); 7.30(dd, J=9.6, 2.4 Hz, 1H); 7.25 (br d, J=8.4 Hz, 2H); 3.95 (q, J=7.2 Hz,2H); 2.53 (s, 3H); 1.15 (t, J=7.2 Hz, 3H).

Step 3: Preparation of (S)-ethyl2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate:To a solution of ethyl2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate(1 g, 2 mmol) and (R)-(+)-2-methyl-CBS-oxazaborolidine (0.11 g, 0.4mmol) in toluene (7 mL) cooled to −20° C. was added a solution offreshly distilled catecholborane (0.29 mL, 2.6 mmol) in toluene (3 mL).After 3 h, saturated Na₂CO₃ (10 mL) was added, the mixture allowed towarm to room temperature and the layers separated. Following extractionwith EtOAc, the combined organic layers were washed with additionalsaturated Na₂CO₃ (15 mL portions) until the washing was no longercolored and then once with saturated NH₄Cl (15 mL). After drying overanhydrous MgSO₄, the solution was absorbed onto silica gel in vacuo andpurified by Yamazen column chromatography (10-65% EtOAc/Hex) to afford0.61 g (61%, 98% ee) of the title compound as a colorless amorphoussolid. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.72 (s, 1H); 7.69 (d, J=2.4 Hz, 1H);7.50 (m, 2H); 7.37 (d, J=9.2 Hz, 1H); 7.30 (m, 2H); 7.19 (dd, J=9.2, 2.4Hz, 1H); 5.21 (d, J=2 Hz, 1H); 4.21 (m, 2H); 3.25 (d, J=2 Hz, 1H); 2.53(s, 3H); 1.22 (t, J=7.2 Hz, 3H).

Step 4: Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:Perchloric acid (70%, 0.28 mL, 3.2 mmol) was added to a solution of(S)-ethyl 2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate (0.82 g, 1.6 mmol) in tert-butylacetate (5 mL) at room temperature. After 3 h, solid NaHCO₃ was addedand the slurry stirred vigorously for 30 min. Saturated NaHCO₃ was addedslowly until the mixture was pH ˜8. Following extraction of the organiclayer with EtOAc, the combined organics were washed with brine, driedover anhydrous MgSO₄ and concentrated in vacuo. The resulting residuewas purified by Yamazen column chromatography (0-35% EtOAc/Hex) toproduce 0.52 g (57%) of the title compound as an amorphous solid.¹H-NMR: 400 MHz, (CDCl₃) δ: 7.69 (s, 1H); 7.66 (d, J=2.4 Hz, 1H); 7.51(m, 2H); 7.44 (m, 1H); 7.34 (d, J=9.4 Hz, 1H); 7.27 (m, 1H); 7.15 (dd,J=9.4, 2.4 Hz, 1H); 5.12 (s, 1H); 4.17 (m, 2H); 2.63 (s, 3H); 1.23 (t,J=7.2 Hz, 3H); 1.01 (s, 9H).

Step 5: Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-4-yl)naphthalen-2-yl)acetate:A solution of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(0.060 g, 0.11 mmol), pyridin-4-ylboronic acid (0.020 g, 0.16 mmol), andPd(PPh₃)₄ (0.012 g, 0.011 mmol) in DME (1 mL) was treated with 2 M K₂CO₃(0.16 mL, 0.32 mmol) and sparged with Ar for 10 min. Following microwaveheating at 110° C. for 20 min, the reaction mixture was absorbed ontosilica gel in vacuo and purified by Yamazen column chromatography(15-100% EtOAc/Hex) to afford 0.043 g (82%) as a colorless glass.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₁ClNO₃: 488.20. found: 488.70.

Step 6: Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-4-yl)naphthalen-2-yl)aceticacid (53): A solution (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-4-yl)naphthalen-2-yl)acetate(0.043 g, 0.088 mmol) in THF/MeOH/H₂O (1 mL each) was treated withLiOH*H₂O (0.025 g, 0.59 mmol) and heated to 50° C. overnight. Theresulting solution was diluted with DMF and purified by preparatoryreverse phase HPLC (Gemini column, 15 to 100% MeCN/H₂O, 0.1% TFA).Lyophilization of appropriate fractions afforded 0.021 g of 53 as anoff-white amorphous powder. ¹H-NMR: 400 MHz, (CD₃CN) δ: 8.77 (br s, 2H);8.37 (br s, 1H); 8.17 (br s, 2H); 7.91 (s, 1H); 7.76 (dd, J=8.8, 2.4 Hz,1H); 7.62-7.54 (m, 3H); 7.46 (d, J=8.8 Hz, 1H); 7.38 (br d, J=8.8 Hz,1H); 5.25 (s, 1H); 2.61 (s, 3H); 0.99 (s, 9H). LCMS-ESI⁻ (m/z):[2M−H]calcd for C₅₆H₅₁Cl₂N₂O₆: 917.31. found: 917.51.

Example 52(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-3-yl)naphthalen-2-yl)aceticacid (54)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-3-yl)naphthalen-2-yl)aceticacid (54):(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-3-yl)naphthalen-2-yl)aceticacid (54) was prepared in a similar fashion to compound 53 of Example 51with the substitution of pyridin-3-ylboronic acid forpyridin-4-ylboronic acid in step 5. The title compound (0.024 g) wasisolated as an amorphous white powder. LCMS-ESI⁻ (m/z): [2M−H]-calcd forC₅₆H₅₁Cl₂N₂O₆: 917.31. found: 917.39. ¹H-NMR: 400 MHz, (CD₃CN) δ: 9.08(s, 1H); 8.74 (d, J=5.2 Hz, 1H); 8.61 (d, J=8 Hz, 1H); 8.19 (s, 1H);7.93-7.88 (m, 1H); 7.84 (s, 1H); 7.66-7.53 (m, 4H); 7.44-7.35 (m, 2H);5.24 (s, 1H); 2.59 (s, 3H); 0.99 (s, 9H).

Example 53(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (55)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (55):(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (55) was prepared in a similar fashion to compound 53 of Example 51with the substitution of pyrimidin-5-ylboronic acid forpyridin-4-ylboronic acid in step 5. The title compound (0.004 g) wasisolated as an amorphous white powder. LCMS-ESF (m/z): [2M−H]calcd forC₅₄H₄₉Cl₂N₄O₆: 919.30. found: 919.76. ¹H-NMR: 400 MHz, (CD₃CN) δ: 9.16(s, 1H); 9.12 (br s, 2H); 8.19 (br s, 1H); 7.85 (br s, 1H); 7.67 (dd.J=9.2H, 1.6 Hz, 1H); 7.61-7.54 (m, 3H); 7.43 (d, J=9.2 Hz, 1H);7.41-7.37 (m, 1H); 5.24 (s, 1H); 2.60 (s, 3H); 0.99 (s, 9H).

Example 54(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1H-pyrazol-5-yl)naphthalen-2-yl)aceticacid (56)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1H-pyrazol-5-yl)naphthalen-2-yl)aceticacid (56):(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1H-pyrazol-5-yl)naphthalen-2-yl)aceticacid (56) was prepared in a similar fashion to compound 53 of Example 51with the substitution of 1H-pyrazol-5-ylboronic acid forpyridin-4-ylboronic acid in step 5. The title compound (0.004 g) wasisolated as an amorphous white powder. LCMS-ESF (m/z): [2M−H]⁻ calcd forC₅₂H₄₉Cl₂N₄O₆: 895.30. found: 895.45. ¹H-NMR: 400 MHz, (CD₃CN) δ: 8.23(br s, 1H); 7.93 (d, J=9.6 Hz, 1H); 7.79 (s, 1H); 7.68 (s, 1H);7.61-7.53 (m, 3H); 7.40-7.35 (m, 1H); 7.30 (d, J=9.6 Hz, 1H); 6.78 (s,1H); 5.22 (s, 1H); 2.57 (s, 3H); 0.99 (s, 9H).

Example 55(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1H-pyrazol-4-yl)naphthalen-2-yl)aceticacid (57)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1H-pyrazol-4-yl)naphthalen-2-yl)aceticacid (57):(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1H-pyrazol-4-yl)naphthalen-2-yl)aceticacid (57) was prepared in a similar fashion to compound 53 of Example 51with the substitution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole forpyridin-4-ylboronic acid in step 5. The title compound (0.004 g) wasisolated as an amorphous white powder. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₆H₂₆ClN₂O₃: 449.95. found: 449.57. ¹H-NMR: 400 MHz, (CD₃CN) δ: 8.03(br s, 2H); 8.00 (br s, 1H); 7.71 (s, 1H); 7.59-7.52 (m, 4H); 7.38-7.34(m, 1H); 7.26 (d, J=9.6 Hz, 1H); 5.20 (1H); 2.56 (3H); 0.98 (s, 9H).

Example 562-tert-Butoxy-2-(1-(4-chlorophenyl)-3,6-dimethylnaphthalen-2-yl)aceticacid (58)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3,6-dimethylnaphthalen-2-yl)aceticacid (58):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3,6-dimethylnaphthalen-2-yl)aceticacid (58) was prepared with a route similar to that described forcompound 53 of Example 51 beginning with3,6-dimethyl-3,4-dihydronaphthalen-1(2H)-one (prepared from1-(3-methylphenyl)propan-2-one) and omitting steps 5 and 6 of Example50, and steps 2 and 5 of Example 51. Step 3 of Example 51 was replacedby treatment with NaBH₄ in EtOH at room temperature to afford racemicmaterial. The title compound was isolated (0.075 g) as a white amorphouspowder. LCMS-ESI (m/z): [M−H]⁻ calcd for C₂₄H₂₄ClO₃: 395.14. found:394.96. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.69-7.61 (m, 1H); 7.58 (s, 1H);7.54 (s, 1H); 7.53-7.46 (m, 2H); 7.30-7.23 (m, 1H); 7.21 (d, J=8.4 Hz,1H); 7.14 (d, J=8.4 Hz, 1H); 5.27 (s, 2H); 2.56 (s, 3H); 2.48 (s, 3H);1.01 (s, 9H).

Example 57(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrimidin-2-yl)naphthalen-2-yl)aceticacid (59)

Step 1. Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)acetate:A solution of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (0.56 g, 1 mmol) in DME (6.5 mL) was treatedwith bis(pinacolato)diboron (0.51 g, 2 mmol), potassium acetate (0.20 g,2 mmol) and PdCl₂(dppf) (0.073 g, 0.1 mmol) and sparged with Ar for 10min. After heating at 100° C. in a sealed vessel for 3 h, the mixturewas allowed to cool to room temperature and absorbed onto silica gel invacuo. Purification by Yamazen column chromatography (2-35% EtOAc/Hex)produced 0.46 g (85%) of the title compound as a colorless oil that wascontaminated with a small amount of pinacol. The material was used insubsequent reactions without further purification. ¹H-NMR: 400 MHz,(CDCl₃) δ: 8.28 (s, 1H); 7.69 (s, 1H); 7.63 (br d, J=8.4 Hz, 1H);7.51-7.42 (m, 3H); 7.29-7.26 (m, 1H); 7.22 (d, J=8.4 Hz, 1H); 5.13 (s,1H); 4.15 (m, 2H); 2.61 (s, 3H); 1.38 (s, 2H); 1.21 (t, J=7.2 Hz, 3H);0.99 (s, 9H).

Step 2: Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrimidin-2-yl)naphthalen-2-yl)acetate:(S)-Ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)acetate(0.072 g, 0.13 mmol), 2-bromopyrimidine (0.032 g, 0.20 mmol),PdCl₂(dppf) (0.005 g, 0.007 mmol) were taken up in 3/1 PhMe/EtOH (1 mL).The resulting solution was treated with 2 M K₂CO₃ (0.35 mL, 0.70 mmol),sealed and sparged with Ar for 10 min. After 2.5 h of heating at 50° C.and cooling to room temperature, the crude reaction mixture was purifiedby Yamazen column chromatography (20-100% EtOAc/Hex) to produce 0.042 g(64%) of a colorless film. LCMS-ESI⁺ (m/z): [M]⁺ calcd for C₂₉H₂₉ClN₂O₃:489.01. found: 489.51.

Step 3: Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrimidin-2-yl)naphthalen-2-yl)aceticacid (59):(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrimidin-2-yl)naphthalen-2-yl)aceticacid (59) was prepared using a method similar to step 6 of Example 51 toafford 0.021 g of 59 as an off-white amorphous powder. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₇H₂₆ClN₂O₃: 461.96. found: 461.34. ¹H-NMR: 400 MHz,(CD₃CN) δ: 8.92 (s, 1H); 8.87 (d, J=4.4 Hz, 2H); 8.36 (dd, J=9.2, 1.6Hz, 1H); 7.94 (s, 1H); 7.61-7.55 (m, 3H); 7.43-7.36 (m, 2H); 7.34 (t,J=4.4 Hz, 1H); 5.24 (s, 1H); 2.59 (s, 3H); 1.0 (s, 9H).

Example 58(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrazin-2-yl)naphthalen-2-yl)aceticacid (60)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrazin-2-yl)naphthalen-2-yl)aceticacid (60):(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyrazin-2-yl)naphthalen-2-yl)aceticacid was prepared in a similar fashion to compound 59 with thesubstitution of 2-chloropyrazine for 2-bromopyrimidine in step 2. Thetitle compound (0.026 g) was isolated as an amorphous pale yellowpowder. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₇H₂₆ClN₂O₃: 461.96. found:461.30. ¹H-NMR: 400 MHz, (CD₃CN) δ: 9.23 (s, 1H); 8.67 (s, 1H); 8.56 (s,2H); 8.05 (d, J=8.8 Hz, 1H); 7.89 (s, 1H); 7.61-7.54 (m, 3H); 7.42 (d,J=8.8 Hz, 1H); 7.39 (br d, J=8.8 Hz, 1H); 5.23 (s, 1H); 2.60 (s, 3H);1.00 (s, 9H).

Example 59(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-6-(imidazo[1,2-a]pyrazin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (61)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-6-(imidazo[1,2-a]pyrazin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (61):(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-6-(imidazo[1,2-a]pyrazin-8-yl)-3-methylnaphthalen-2-yl)aceticacid (61) was prepared in a similar fashion to compound 59 with thesubstitution of 8-chloroimidazo[1,2-a]pyrazine hydrobromide (See Guzi,T. J, Paruch, K., et. al. US 20070105864, p. 121) for 2-bromopyrimidinein step 2. The title compound (0.017 g) was isolated as an amorphouspale yellow powder. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₇ClN₃O₃:500.7. found: 500.0. ¹H-NMR: 400 MHz, (CD₃CN) δ: 9.00 (d, J=1.2 Hz, 1H);8.39 (d, J=4.4 Hz, 1H); 8.20 (dd, J=8.8, 1.2 Hz, 1H); 8.11 (d, J=4.4 Hz,1H); 8.06 (d, J=1.2 Hz, 1H); 7.99 (s, 1H); 7.62-7.56 (m, 3H); 7.38 (d,J=8.8 Hz, 1H); 7.36 (br d, J=8.8 Hz, 1H); 5.25 (s, 1H); 2.58 (s, 3H);0.99 (s, 9H).

Example 60(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(4-methylpyrimidin-5-yl)naphthalen-2-yl)aceticacid (62)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(4-methylpyrimidin-5-yl)naphthalen-2-yl)aceticacid (62):(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(4-methylpyrimidin-5-yl)naphthalen-2-yl)aceticacid (62) was prepared in a similar fashion to compound 59 with thesubstitution of 5-bromo-4-methylpyrimidine for 2-bromopyrimidine in step2. The title compound (0.015 g) was isolated as an amorphous whitepowder. LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₈H₂₈ClN₂O₃: 475.99. found:475.69. ¹H-NMR: 400 MHz, (CD₃CN) δ: 9.13 (br s, 1H); 8.77 (br s, 1H);7.87 (s, 1H); 7.81 (s, 1H); 7.60-7.54 (m, 3H); 7.42-7.37 (m, 3H); 5.25(s, 1H); 2.59 (s, 3H); 2.50 (s, 3H); 1.00 (s, 9H).

Example 61(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-2-yl)naphthalen-2-yl)aceticacid (63)

Step 1. Preparation of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-2-yl)naphthalen-2-yl)acetate:A solution of (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (0.070 g, 0.13 mmol) in NMP (1 mL) was treatedwith LiCl (0.008 g, 0.19 mmol), Pd(PPh₃)₄ (0.014 g, 0.013 mmol) and2-(tributylstannyl)pyridine (85%, 0.071 mL, 0.19 mmol). After spargingthe mixture with Ar for 10 min and microwave heating at 100° C. for 10min, the reaction mixture was allowed to cool to room temperature andloaded directly onto silica for purification by Yamazen columnchromatography (20-100% EtOAc/Hex) to produce 0.015 g (25%) as acolorless film. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₁ClNO₃: 488.20.found: 488.90.

Step 2. Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-2-yl)naphthalen-2-yl)aceticacid (63):(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-2-yl)naphthalen-2-yl)aceticacid (63) was prepared using a method similar to step 6 of Example 51 toafford 0.0041 g of 63 as an off-white amorphous powder. LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₈H₂₇ClNO₃: 460.97. found: 460.70. ¹H-NMR: 400 MHz,(CD₃CN) δ: 8.75 (d, J=4.4 Hz, 1H); 8.49 (br s, 1H); 8.07-7.96 (m, 3H);7.87 (s, 3H); 7.60-7.53 (m, 3H); 7.46 (t, J=5.6 Hz, 1H); 7.40 (d, J=8.8Hz, 1H); 7.39 (br s, 1H); 5.23 (s, 1H); 2.59 (s, 3H); 0.99 (s, 9H).

Example 62(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-4-yl)naphthalen-2-yl)aceticacid (64)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-4-yl)naphthalen-2-yl)aceticacid (64):(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-4-yl)naphthalen-2-yl)aceticacid (64) was prepared in a similar fashion to compound 63 with thesubstitution of 1-methyl-4-(tributylstannyl)-1H-imidazole for2-(tributylstannyl)pyridine in step 1. The title compound (0.026 g) wasisolated as an amorphous white powder. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₇H₂₈ClN₂O₃: 463.98. found: 463.86. ¹H-NMR: 400 MHz, (CD₃CN) δ: 6.46(br s, 1H); 8.24 (br s, 1H); 7.73 (br s, 1H); 7.65 (s, 1H); 7.62-7.51(m, 4H); 7.36-7.25 (m, 2H); 5.21 (s, 1H): 3.85 (s, 3H); 2.56 (s, 3H);0.97 (s, 9H).

Example 63(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-5-yl)naphthalen-2-yl)aceticacid (65)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-5-yl)naphthalen-2-yl)aceticacid (65):(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-5-yl)naphthalen-2-yl)aceticacid (65) was prepared in a similar fashion to compound 63 with thesubstitution of 1-methyl-5-(tributylstannyl)-1H-imidazole for2-(tributylstannyl)pyridine in step 1. The title compound (0.026 g) wasisolated as an amorphous white powder. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₇H₂₈ClN₂O₃: 463.98. found: 463.81. ¹H-NMR: 400 MHz, (CD₃CN) δ: 8.54(s, 1H); 7.99 (s, 1H); 7.84 (s, 1H): 7.62-7.50 (m, 3H); 7.45-7.32 (m,3H), 5.24 (s, 1H); 3.80 (s, 3H); 2.60 (s, 3H); 0.99 (s, 9H).

Example 642-(1,6-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic

Step 1. Preparation of ethyl2-(6-bromo-3-methyl-1-(perfluorobutyl-sulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate:A solution of ethyl2-(6-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate(0.78 g, 1.7 mmol; prepared similarly to(1-hydroxy-5-methoxy-3-methyl-naphthalen-2-yl)-(4-methoxybenzyloxy)aceticacid ethyl ester of Example 32 beginning with1-(3-bromophenyl)propan-2-one) in DCM (17 mL) was cooled to −78° C. andtreated with DIPEA (0.44 mL, 2.6 mmol) and perfluorobutanesulfonicanhydride (0.68 mL, 2.2 mmol). The resulting slurry was allowed toslowly warm to room temperature overnight. Saturated NaHCO₃ was addedand the mixture extracted with EtOAc. The combined organics were washedwith brine, dried over anhydrous MgSO₄ and concentrated in vacuo. Theresidue was purified via Yamazen column chromatography (0-15% EtOAc/Hex)to afford 0.52 g (95%) of the title compound as a yellow solid that wasused without further purification. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.97 (d,J=6.4 Hz, 1H); 7.94 (d, J=9.2 Hz, 1H); 7.66 (dd, J=9.2, 6.4 Hz, 1H);7.59 (s, 1H); 5.78 (br s, 1H); 4.31 (m, 1H); 4.22 (m, 1H); 3.39 (br s,1H): 2.50 (s, 3H); 1.20 (t, J=7.2 Hz, 3H).

Step 2. Preparation of ethyl2-(6-bromo-3-methyl-1-(perfluorobutyl-sulfonyloxy)naphthalen-2-yl)-2-oxoacetate:A solution of ethyl2-(6-bromo-3-methyl-1-(perfluorobutylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate(0.52 g, 0.84 mmol) in DCM (8.5 mL) was treated with Dess-Martinperiodinane (0.43 g, 1.01 mmol) at room temperature. After 1.5 h, a 1/1mixture of saturated NaHCO₃ and saturated Na₂S₂O₃ (10 mL) was added andthe slurry allowed to stir at room temperature for 10 min. The reactionwas further diluted with water and DCM and the aqueous layer extractedwith DCM. The combined organics were washed with water, brine, and driedover anhydrous MgSO₄. After concentration in vacuo, the residue waspurified using Yamazen column chromatography (0-15% EtOAc/Hex) toproduce 0.38 g (73%) of the title compound as an amorphous solid.¹H-NMR: 400 MHz, (CDCl₃) δ: 8.04 (s, 1H); 7.97 (d, J=9.2 Hz, 1H); 7.72(d, J=9.2 Hz, 1H); 7.68 (s, 1H); 4.41 (q, J=7.2 Hz, 2H); 2.50 (s, 3H);1.39 (t, J=7.2 Hz, 3H).

Step 3. Preparation of ethyl2-(1,6-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate: Asolution of ethyl2-(6-bromo-3-methyl-1-(perfluorobutylsulfonyl-oxy)naphthalen-2-yl)-2-oxoacetate(0.379 g, 0.612 mmol), 4-chlorophenylboronic acid (0.105 g, 0.67 mmol),potassium carbonate (0.254 g, 1.84 mmol), and Pd(dppf)Cl₂ (0.022 g,0.031 mmol) was prepared in PhMe (3 mL), EtOH (1.5 mL) and water (1.5mL). The dark brown solution was sparged with argon for 10 min, thenallowed to stir at room temperature for 2.5 h. Following purification,the product was determined to be a mixture of mono and bis substitution.The mixture was resubmitted to reaction conditions and was heated to 50°C. for 2 h. After cooling to room temperature, the reaction was dilutedwith EtOAc, and washed with water. The organic layer was absorbed ontosilica gel in vacuo and purified by Yamazen column chromatography (0-20%EtOAc/Hex) to afford 0.145 g (53%) of the title compound as an amorphoussolid. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.98 (s, 1H); 7.78 (s, 1H); 7.64-7.56(m, 4H); 7.48-7.41 (m, 4H); 7.30-7.22 (m, 2H); 3.91 (q, J=7.2 Hz, 2H);2.51 (s, 3H); 1.12 (t, J=7.2 Hz, 3H).

Step 4. Preparation of ethyl2-(1,6-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate: Asolution of ethyl2-(1,6-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (0.145g, 0.31 mmol) in EtOH (2 mL) and DCM (1 mL) at 0° C. was treated withNaBH₄ (0.018 g, 0.048 mmol) in one portion. The reaction was allowed towarm to room temperature over 30 min and treated with saturated NaHCO₃(3 mL). The mixture was stirred vigorously for 30 min and then dilutedwith EtOAc and water. Following extraction with EtOAc, the organics werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated toproduce 0.121 g (84%) of the title compound as a white foam that wasused in subsequent steps without further purification. ¹H-NMR: 400 MHz,(CDCl₃) δ: 7.94 (s, 1H); 7.73 (s, 1H); 7.60 (d, J=8.4 Hz, 2H); 7.56-7.42(m, 6H); 7.38-7.30 (m, 2H); 5.23 (s, 1H); 4.20 (m, 2H); 2.52 (s, 3H);1.21 (t, J=7.2 Hz, 3H).

Steps 5 and 6. Preparation of2-(1,6-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (66): Step 5 was performed similarly to step 4 of Example 51. Step6 was performed similarly to Step 6 of Example 51 with heating at 60° C.overnight to produce 0.053 g of the title compound as an amorphous whitepowder. LCMS-ESI⁻ (m/z): [2M-2H+Na]⁻ calcd for C₅₈Hs₅₀Cl₄NaO₆: 1007.82.found: 1007.05. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.93 (br s, 1H); 7.23 (s,1H); 7.60 (br d, J=8.8 Hz, 2H); 7.58-7.49 (m, 3H); 7.43 (br d, J=8.8 Hz,2H); 7.39 (br d, J=8.8 Hz, 1H); 7.32 (br s, 1H); 5.30 (s, 1H); 2.60 (s,3H); 1.03 (s, 9H).

Example 652-tert-Butoxy-2-(6-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (67)

Steps 1-4. Preparation of methyl2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate:p-methoxybenzyl alcohol (5.9 mL, 47.2 mmol) was diluted with THF (180mL) and cooled to −78° C. under an Ar atmosphere. KHMDS (0.5 M PhMesolution, 71 mL, 35.4 mmol) was added dropwise over 20 min and thesolution allowed to age for 20 min at this temperature to produce anopaque white suspension. A solution of (E)-ethyl2-((3R,4R)-4-bromo-6-chloro-3-methyl-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)acetate(4.22 g, 11.8 mmol; prepared similarly to(4-bromo-5-methoxy-3-methyl-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene)aceticacid ethyl ester of Example 32 beginning with1-(3-chlorophenyl)propan-2-one) was prepared in THF (50 mL) and added tothe reaction at a rate that maintained an internal temperature less than−65° C. After 5 min, propionic acid (10 mL, 134 mmol) was added and thereaction warmed to room temperature over 1.5 h prior to dilution withwater (150 mL). Extraction of the aqueous layer with ethyl acetate wasfollowed by washing of the combined organics with saturated NaHCO₃,water and brine. Following drying over anhydrous MgSO₄ and concentrationin vacuo, the resulting residue was eluted on Yamazen columnchromatography to produce an inseparable mixture of products (5.56 g)that included ethyl2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate,4-methoxybenzyl2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate,ethyl2-((3R,4R)-4-bromo-6-chloro-3-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate,and 4-methoxybenzyl2-((3R,4R)-4-bromo-6-chloro-3-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate.

This material was taken up in chloroform (60 mL) and treated with DBU(5.1 mL, 33.9 mmol) at room temperature. After 1 h, 5% citric acidsolution was added and the aqueous phase extracted with DCM. Thecombined organics were washed with brine, dried over anhydrous MgSO₄,and concentrated in vacuo. Following elution by Yamazen columnchromatography, 1.68 g of material was recovered that was primarily amixture of ethyl2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetateand 4-methoxybenzyl2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate.This material was taken up in THF/MeOH/H₂O (10/5/5 mL respectively) andtreated with LiOH monohydrate (0.86 g, 20.5 mmol). The mixture washeated to 50° C. for 1.5 h and then allowed to cool before acidifyingwith 2 M HCl solution. The aqueous phase was extracted with EtOAc. Thecombined organics were washed with brine, dried over anhydrous Na₂SO₄and concentrated in vacuo to afford2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)aceticacid (0.658 g) as a white foam that was used in the next step withoutfurther purification.2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)aceticacid (0.658 g, 1.7 mmol) was diluted in DCM and MeOH (20 mL each) andtreated with TMSCHN₂ (2 M in hexanes) until the reaction remained abright yellow color. After 45 min, glacial acetic acid was addeddropwise until the reaction faded to a pale yellow color, indicating anyremaining TMSCHN₂ had been destroyed. The reaction was absorbed ontosilica gel in vacuo and was purified by Yamazen column chromatography toproduce 0.649 g (14% over four steps) of the title compound as anamorphous white solid that was used without further purification.¹H-NMR: 400 MHz, (CDCl₃) δ: 8.54 (s, 1H); 8.18 (d, J=8.8 Hz, 1H); 7.63(d, J=1.6 Hz, 1H); 7.33 (dd, J=8.8, 1.6 Hz, 1H); 7.27 (d, J=8.8 Hz, 2H);7.09 (s, 1H); 6.90 (s, J=8.8 Hz, 2H); 5.38 (s, 1H); 4.65 (AB d, J=11.2Hz, 1H); 4.59 (AB d, J=11.2 Hz, 1H); 3.83 (s, 3H); 3.73 (s, 3H); 2.39(s, 3H).

Step 5. Preparation of methyl2-(6-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate:A solution of methyl2-(6-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate(0.649 g, 1.62 mmol) in DCM (16 mL) under Ar was cooled to −78° C. andtreated with 2,6-lutidine (0.56 mL, 4.9 mmol) andtrifluoromethanesulfonic anhydride (1.15 mL, 2.4 mmol). After 4 h,saturated NaHCO₃ solution was added at −78° C. and the reaction warmedto room temperature with stirring. Following dilution with water andDCM, the aqueous layer was extracted with DCM and the combined organicswere washed with brine, dried over anhydrous MgSO₄ and concentrated invacuo. The residue was purified using Yamazen column chromatography(5-25% EtOAc/hex) to produce 0.765 g of the title compound as anamorphous solid. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.97 (d, J=9.2 Hz, 1H);7.78 (d, J=1.6 Hz, 1H); 7.60 (s, 1H); 7.53 (dd, J=9.2, 1.6 Hz, 1H); 7.24(d, J=8.8 Hz, 2H); 6.82 (d, J=8.8 Hz, 2H); 5.62 (s, 1H); 4.66 (ABd,J=11.2 Hz, 1H); 4.59 (ABd, J=11.2 Hz, 1H); 3.78 (s, 3H); 3.75 (s, 3H);2.55 (s, 3H).

Step 6. Preparation of methyl2-(6-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate:Methyl2-(6-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate(0.106 g, 0.2 mmol), 4-chlorophenylboronic acid (0.038 g, 0.24 mmol),and Pd(PPh₃)₄ (0.23 g, 0.02 mmol) were combined in DME (1 mL) andtreated with 2 M K₂CO₃ solution (1.2 mL, 0.6 mmol). The resultingmixture was sparged with Ar for 10 minutes and then heated in amicrowave reactor at 100° C. for 20 min. The resulting mixture wasloaded directly onto silica gel and purified with Yamazen columnchromatography (3-25% EtOAc/Hex) to produce 0.051 g of the titlecompound as an amorphous foam. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.67 (d,J=2.4 Hz, 1H); 7.60 (s, 1H); 7.42 (dd, J=8, 2.4 Hz, 1H); 7.32 (dd,J=8.2, 2.4 Hz, 1H); 7.28 (dd (obscured), J=8.2, 2.4 Hz, 1H); 7.22 (dd,J=8.8, 2 Hz, 1H); 7.15 (d, J=8.8 Hz, 1H); 7.08 (br d, J=8.4 Hz, 2H);6.99 (dd, J=8, 2 Hz, 1H); 6.79 (br d, J=8.4 Hz, 2H); 5.05 (s, 1H); 4.46(ABd, J=11.6 Hz, 1H); 4.35 (ABd, J=11.6 Hz, 1H); 3.82 (s, 3H); 3.72 (s,3H); 2.57 (s, 3H).

Step 7. Preparation of methyl2-(6-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate:A solution of methyl2-(6-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetatein DCM (1 mL) was treated with trifluoroacetic acid (0.052 mL, 0.67mmol) at room temperature. After 45 min, the reaction was diluted withDCM and treated with saturated NaHCO₃. After separation the organiclayer was absorbed directly onto silica gel in vacuo. Purification viaYamazen column chromatography yielded 0.039 g of a colorless film.¹H-NMR: 400 MHz, (CDCl₃) δ: 7.76 (d, J=1.6 Hz, 1H); 7.60 (s, 1H);7.52-7.45 (m, 2H); 7.34-7.27 (m, 2H); 7.25 (dd (obscured) J=8.8, 2 Hz,1H); 7.20 (d, J=8.8 Hz, 1H); 5.23 (s, 1H); 3.74 (s, 3H), 2.49 (s, 3H).

Steps 8 and 9. Preparation of2-tert-butoxy-2-(6-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (67): Step 8 was performed similarly to Step 4 of Example 51. Step9 was performed similarly to Step 6 of Example 51 with appropriateadjustments for scale to produce 0.006 g of a racemic mixture of thetitle compound as an amorphous white powder. LCMS-ESf (m/z): [M−H]⁻calcd for C₂₃H₂₁Cl₂O₃: 415.09; found: 415.56. ¹H-NMR: 400 MHz, (CD₃CN)δ: 7.85 (d, J=2 Hz, 1H); 7.70 (s, 1H); 7.59-7.50 (m, 3H); 7.36-7.23 (m,3H); 5.20 (s, 1H); 2.56 (s, 3H); 0.97 (s, 9H).

Example 66(S)-2-tert-Butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (68A) and(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (68B)

Step 1: Preparation of (+)-(S)-methyl2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate.Methyl2-(6-chloro-3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate(1.24 g, 2.32 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronicacid hydrochloride (0.70 g, 2.79 mmol) and Pd(PPh₃)₄ (0.27 g, 0.232mmol) were combined in DME (6.2 mL) and treated with 2 M K₂CO₃ (4.6 mL,9.3 mmol). After sparging for 10 min with Ar, the reaction was heated ina microwave reactor at 100° C. for 20 min. The reaction mixture was thenabsorbed directly onto silica gel and purified by Yamazen columnchromatography (20-59% EtOAc/Hex) to provide two diastereomer pairs aswhite amorphous solids. Anti racemate: 0.348 g; ¹H-NMR: 400 MHz, (CDCl₃)δ: 8.70 (d, J=4.4 Hz, 1H); 7.75 (d, J=2 Hz, 1H); 7.63 (s, 1H); 7.35 (d,J=8 Hz, 1H); 7.15 (d, J=8.8 Hz, 2H); 7.09 (d, J=4.4 Hz, 1H); 7.06 (dd,J=8, 2 Hz, 1H); 6.99 (d, J=8 Hz, 1H); 6.95 (d, J=8.8 Hz, 1H); 6.81 (d,J=8.8 Hz, 2H); 4.97 (s, 1H); 4.57 (t, J=5.6 Hz, 2H); 4.53 (AX d, J=11.2Hz, 1H); 4.24 (AX d, J=11.2 Hz, 1H); 3.81 (s, 3H); 3.58 (s, 3H); 3.33(t, J=5.6 Hz, 2H); 2.59 (s, 3H).

Syn racemate: 0.166 g; ¹H-NMR: 400 MHz, (CDCl₃) δ: 8.64 (d, J=4 Hz, 1H);7.74 (d, J=2 Hz, 1H); 7.62 (s, 1H); 7.57 (d, J=8 Hz, 1H); 7.08 (br d,J=4 Hz, 1H); 7.04 (dd, J=8, 2 Hz, 1H); 7.03 (d, J=9 Hz, 1H); 6.87 (d,J=9 Hz, 1H); 6.77 (d, J=8.4 Hz, 2H); 6.57 (d, J=8.4 Hz, 2H); 5.04 (s,1H); 4.52 (m, 2H); 4.23 (AM d, J=12.4 Hz, 1H); 3.99 (AM d, J=12.4 Hz,1H); 3.71 (s, 3H); 3.67 (s, 3H); 3.31 (m, 2H); 2.56 (s, 3H).

Step 2. (±)-(S)-methyl2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetatewas prepared similarly to Step 7 of Example 65 to produce 0.238 g as anamorphous foam. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₅H₂₁ClNO₄: 434.89.found: 434.53. The syn racemate was treated in the same fashion toproduce 0.106 g of an amorphous foam. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₅H₂₁ClNO₄: 434.89. found: 434.57.

Step 3. (S)-methyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetatewas prepared similarly to Step 4 of Example 51 with appropriateadjustments for scale to produce 0.154 g of the anti enantiomers as acolorless film, which were separated by preparatory HPLC on a ChiracelOJ-H column (4.6×250 mm, 15 mL/min) with 100% MeOH elution to produce0.063 g of (R)-methyl2-tert-butoxy-2-((S)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetateand 0.057 g of (S)-methyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetateas colorless films. LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₉H₂₉ClNO₄:490.99. found: 490.59. The syn enantiomers were treated in a similarfashion to produce 0.047 g of a colorless film as a racemic mixture.LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₉ClNO₄: 490.99. found: 490.62.

Step 4.(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (68A) was prepared in a similar fashion to step 6 of Example 51with appropriate adjustments for scale to produce 0.043 g of a paleyellow amorphous powder. LCMS-ESF (m/z): [M−H]⁻ calcd for C₂₈H₂₅ClNO₄:474.96. found: 474.37. ¹H-NMR: 400 MHz, (CD₃CN) δ: 8.58 (d, J=5.2 Hz,1H); 7.93 (d, J=2 Hz, 1H); 7.75 (d, J=8.8 Hz, 1H); 7.60 (d, J=5.2 Hz,1H); 7.34 (d, J=8 Hz, 1H); 7.20 (dd, J=8, 2 Hz, 1H); 6.88 (d, J=8.8 Hz,1H); 5.16 (s, 1H); 4.64 (m, 2H); 3.52 (t, J=5.6 Hz, 2H); 2.68 (s, 3H);0.92 (s, 9H).

Step 5 and 6. Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (68B): A solution of (S)-methyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(0.020 g, 0.041 mmol) in toluene (0.5 mL) and EtOH (0.25 mL) was treatedwith trimethylboroxine (0.021 mL, 0.123 mmol), S-Phos precatalyst (0.001g, 0.002 mmol) and K₂CO₃ (2 M, 0.105 mL, 0.21 mmol). The mixture wassparged with Ar for 10 min and then heated in a microwave reactor at100° C. for 30 min. The reaction mixture was loaded directly onto silicagel and eluted with Yamazen column chromatography. The collectedmaterial was taken up in THF/MeOH/H₂O (1 mL each) and treated withLiOH*H₂O (0.030 g, 0.72 mmol) at 50° C. overnight. Followingpurification by preparatory HPLC to produce 0.007 g of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (68B). LCMS-ESIf (m/z): [M+H]⁺ calcd for C₂₉H₃₀NO₄: 456.55. found:456.15. ¹H-NMR: 400 MHz, (CD₃CN) δ: 8.56 (d, J=4.8 Hz, 1H); 7.79 (s,1H); 7.72 (br d, J=8, 1H); 7.65 (s, 1H); 7.53 (br s, 1H); 7.30 (d, J=8Hz, 1H); 7.08 (d, J=8 Hz, 1H); 6.76 (d, J=8 Hz, 1H); 5.15 (br s, 1H);4.62 (m, 2H); 3.49 (t, J=6 Hz, 2H); 2.65 (s, 3H); 2.44 (s, 3H); 0.92 (s,9H).

Example 672-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (69)

Step 1. Preparation of ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate:To a solution of ethyl2-(7-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-(4-methoxybenzyloxy)acetate(4.0 g, 8.7 mmol) in CH₂Cl₂ (40 mL) at −78° C. was added triethylamine(1.46 mL, 10.5 mmol) and trifluoromethanesulfonic anhydride (1.0 Msolution in CH₂Cl₂, 9.6 mL, 9.6 mmol). After 15 min, a saturatedsolution of NH₄Cl was added. The mixture was warmed to room temperature.The layers were separated, dried, filtered, and concentrated in vacuo.The crude product was taken on without further purification. ¹H-NMR: 400MHz, (CDCl₃) δ: 8.30 (s, 1H), 7.77 (m, 3H), 7.35 (d, J=9 Hz, 2H), 6.94(d, J=9 Hz, 2H), 5.73 (s, 1H), 4.73 (m, 2H), 4.36 (m, 2H), 3.89 (s, 3H),2.67 (s, 3H), 1.32 (t, J=7 Hz, 3H).

Step 2. Preparation of ethyl2-(7-bromo-3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate:To a solution of ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-(4-methoxybenzyl-oxy)acetate(8.7 mmol from previous step) in CH₂Cl₂ (40 mL) was addedtrifluoroacetic acid (TFA) (4 mL). After 1.5 h, water was added (40 mL).The layers were separated. The organic layer was washed with a saturatedsolution of NaHCO₃.

The organic layer was dried, filtered, and concentrated in vacuo. Thecrude product was taken on without further purification. ¹H-NMR: 400MHz, (CDCl₃) δ: 8.21 (s, 1H), 7.65 (m, 3H), 5.79 (s, 1H), 4.27 (m, 2H),2.48 (s, 3H), 1.20 (t, J=7 Hz, 3H). ¹⁹F-NMR: 377 MHz, (CDCl₃) δ: −73.0.

Step 3. Preparation of ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate:To a solution of ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate(˜8.7 mmol) in CH₂Cl₂ (40 mL) was added Dess-Martin periodinane (4.07 g,9.6 mmol). After 1.5 h, a saturated solution of Na₂S₂O₄ (20 mL) andwater (20 mL) was added. The mixture was stirred vigorously for 30 min.The layers were separated, and the organic layer was dried, filtered,and concentrated in vacuo. The crude material was purified by columnchromatography (EtOAc/hexanes) to give 3.22 g (79%) of the titledcompound. ¹H-NMR: 400 MHz, (CDCl₃) δ: 8.22 (s, 1H), 7.70 (m, 3H), 4.41(q, J=7 Hz, 2H), 2.47 (s, 3H), 1.39 (t, J=7 Hz, 3H). ¹⁹F-NMR: 377 MHz,(CDCl₃) δ: −73.2.

Step 4. Preparation of ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate: Toa solution of ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate(235 mg, 0.50 mmol) in PhCH₃ (1.2 mL), EtOH (0.6 mL), H₂O (0.6 mL) wasadded 4-chlorophenylboronic acid (86 mg, 0.55 mmol), K₂CO₃ (207 mg, 1.5mmol), and PdCl₂dppf (11 mg, 0.015 mmol). The reaction mixture wasstirred at room temperature for 2 h and was then diluted with H₂O andEtOAc. The layers were separated, and the organic layer was dried,filtered, and concentrated in vacuo. The crude material was purified bycolumn chromatography (EtOAc/hexanes) to give 129 mg (60%) of the titledcompound and 37 mg of the bis-coupled product (ethyl2-(1,7-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate).¹H-NMR: 400 MHz, (CDCl₃) δ: 7.60-7.72 (m, 4H), 7.45 (m, 2H), 7.23 (m,2H), 3.93 (q, J=7 Hz, 2H), 2.48 (s, 3H), 1.13 (t, J=7 Hz, 3H).

Step 5. Preparation of ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate:To a solution of ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate (1.6g, 2.78 mmol) in EtOH (10 mL) was added sodium borohydride (NaBH₄) (157mg, 4.17 mmol). After 20 min, a saturated solution of NH₄Cl was addedand EtOAc. The layers were separated, and the organic layer was dried,filtered, and concentrated in vacuo. The crude material was taken onwithout further purification. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.64 (m, 2H),7.45 (m, 3H), 7.39 (s, 1H), 7.28 (m, 2H), 5.18 (s, 1H), 4.17 (m, 2H),2.48 (s, 3H), 1.20 (t, J=7 Hz, 3H).

Step 6. Preparation of ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate:To a solution of ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate(˜2.78 mmol) in t-BuOAc (14 mL) was added perchloric acid (HClO₄) (334μL, 5.56 mmol). After 3 h, water was added. The layers were separated,and the organic layer was dried, filtered, and concentrated in vacuo.The crude material was purified by column chromatography (EtOAc/hexanes)to give 877 mg of the titled compound. ¹H-NMR: 400 MHz, (CDCl₃) δ: 7.62(m, 2H), 7.51 (m, 4H), 7.27 (m, 2H), 5.09 (s, 1H), 4.15 (m, 2H), 2.59(s, 3H), 1.19 (t, J=7 Hz, 3H), 1.00 (s, 9H).

Step 7. Preparation of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetate:To a solution of ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(30 mg, 0.061 mmol) in THF (1 mL) was added 2-methylbut-3-yn-2-ol (15mg, 0.18 mmol), CuI (1 mg, 0.006 mmol), Pd(PPh₃)₄ (3 mg, 0.003 mmol),and Et₃N (50 μL, 0.36 mmol). The reaction mixture was stirred at 65° C.for 1 h. A saturated solution of NH₄Cl was added. The layers wereseparated, and the organic layer was dried, filtered, and concentratedin vacuo. The crude material was purified by column chromatography(EtOAc/hexanes) to give 22 mg of the titled compound. ¹H-NMR: 400 MHz,(CD₃OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.57 (m, 2H), 7.48 (m,1H), 7.40 (d, J=9 Hz, 1H), 7.29 (d, J=9 Hz, 1H), 7.24 (s, 1H), 5.15 (s,1H), 4.16 (m, 2H), 2.57 (s, 3H), 1.51 (s, 6H), 1.20 (t, J=7 Hz, 3H),0.99 (s, 9H).

Step 8. Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (69): To a solution of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetate(22 mg, 0.045 mmol) in 2:2:1 THF/MeOH/H₂O (1 mL total) was added a NaOHsolution (4 M, 0.2 mL). The reaction mixture was stirred at 60° C. for 2h. The mixture was partially concentrated and diluted with MeCN and H₂Oand purified by reverse phase HPLC (MeCN/H₂O) to give 12 mg of thetitled compound. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67(s, 1H), 7.57 (m, 3H), 7.38 (d, J=9 Hz, 1H), 7.30 (d, J=9 Hz, 1H), 7.26(s, 1H), 5.16 (s, 1H), 2.60 (s, 3H), 1.51 (s, 6H), 0.98 (s, 9H). HPLC(Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5 min run): t_(R)(min)=3.40.

Example 682-(1,7-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (70)

Preparation of2-(1,7-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (70):2-(1,7-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (70)was prepared by the method of Example 67. Steps 5, 6 and 8 fromethyl 2-(1,7-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate,which was a byproduct in Step 4. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.88 (d,J=8 Hz, 2H), 7.72 (m, 2H), 7.58 (m, 3H), 7.44 (m, 3H), 7.38 (d, J=8 Hz,2H), 5.19 (s, 1H), 2.62 (s, 3H), 0.98 (s, 9H). HPLC (Kinetex 2.6u,50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5 min run): t_(R) (min)=3.83.

Example 692-(7-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (71)

Preparation of2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (71):2-(7-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (71) was prepared by the method of Example 67 skipping step 7 fromethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate.¹H-NMR: 400 MHz, (CD₃OD) δ: 7.71 (m, 2H), 7.58 (m, 3H), 7.52 (dd, J=9, 2Hz, 1H), 7.33 (m, 2H), 5.15 (s, 1H), 2.59 (s, 3H), 0.97 (s, 9H). HPLC(Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5 min run): t_(R)(min)=3.67.

Example 702-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3,3-dimethylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (72)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3,3-dimethylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (72):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3,3-dimethylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (72) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing t-butylacetylene. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.70 (d, J=8 Hz,1H), 7.65 (s, 1H), 7.57 (m, 3H), 7.33 (m, 2H), 7.19 (s, 1H), 5.16 (s,1H), 2.59 (s, 3H), 1.27 (s, 9H), 0.97 (s, 9H). HPLC (Kinetex 2.6u,50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5 min run): t_(R) (min)=3.78.

Example 712-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclo-pentyl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (73)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (73):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (73) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 1-ethynylcyclopentanol. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.73 (d, J=9Hz, 1H), 7.67 (s, 1H), 7.56 (m, 3H), 7.39 (d, J=8 Hz, 1H), 7.30 (d, J=8Hz, 1H), 7.26 (s, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.93 (m, 4H), 1.78(m, 4H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100%MeCN/H₂O+0.05% HOAc, 5 min run): t_(R) (min)=3.56.

Example 722-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopentylethynyl)-3-methylnaphthalen-2-yl)aceticacid (74)

2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopentylethynyl)-3-methylnaphthalen-2-yl)aceticacid (74):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopentylethynyl)-3-methylnaphthalen-2-yl)aceticacid (74) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing ethynylcyclopentane.

¹H-NMR: 400 MHz, (CD₃OD) δ: 7.56-7.71 (m, 6H), 7.32 (m, 1H), 7.19 (s,1H), 5.16 (s, 1H), 2.79 (m, 1H), 2.59 (s, 3H), 1.57-1.75 (m, 8H), 0.97(s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5min run): t_(R) (min)=4.10.

Example 732-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopropylethynyl)-3-methylnaphthalen-2-yl)aceticacid (75)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(cyclopropylethynyl)-3-methylnaphthalen-2-yl)aceticacid (75):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(cyclopropylethynyl)-3-methylnaphthalen-2-yl)aceticacid (75) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing ethynylcyclopropane. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.69 (m, 2H),7.57 (m, 3H), 7.32 (m, 2H), 7.18 (s, 1H), 5.16 (s, 1H), 2.59 (s, 3H),1.42 (br m, 1H), 0.97 (s, 9H), 0.83 (br m, 2H), 0.68 (br m, 2H). HPLC(Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5 min run): t_(R)(min)=3.78.

Example 742-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2-yl)aceticacid (76)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2-yl)aceticacid (76):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2-yl)aceticacid (76) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing tributyl(vinyl)tin and without triethylamine. ¹H-NMR: 400 MHz,(CD₃OD) δ: 7.74 (d, J=9 Hz, 1H), 7.65 (m, 2H), 7.55 (m, 3H), 7.32 (d,J=9 Hz, 1H), 7.13 (s, 1H), 6.65 (dd, J=18, 11 Hz, 1H), 5.71 (d, J=18 Hz,1H), 5.19 (d, J=11 Hz, 1H), 5.17 (s, 1H), 2.59 (s, 3H), 0.98 (s, 9H).HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5 min run):t_(R) (min)=3.99.

Example 752-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(2-methylprop-1enyl)naphthalen-2-yl)aceticacid (77)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(2-methylprop-1-enyl)naphthalen-2-yl)aceticacid (77):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(2-methylprop-1-enyl)naphthalen-2-yl)aceticacid (77) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolaneand K₂CO₃ instead of triethylamine, and toluene, ethanol, water as asolvent mixture. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.69 (d, J=8 Hz, 1H), 7.61(s, 1H), 7.54 (m, 3H), 7.27 (m, 2H), 7.02 (s, 1H), 6.23 (s, 1H), 5.18(s, 1H), 2.57 (s, 3H), 1.83 (s, 3H), 1.68 (s, 3H), 0.97 (s, 9H). HPLC(Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5 min run): t_(R)(min)=3.98.

Example 762-tert-Butoxy-2-(1-(4-chlorophenyl)-3,7-dimethylnaphthalen-2-yl)aceticacid (78)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3,7-dimethylnaphthalen-2-yl)aceticacid (78):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3,7-dimethylnaphthalen-2-yl)aceticacid (78) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing trimethylboroxine and K₂CO₃ instead of triethylamine, and toluene,ethanol, water as a solvent mixture. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.65(d, J=8 Hz, 1H), 7.61 (s, 1H), 7.53 (m, 3H), 7.27 (m, 2H), 6.98 (s, 1H),5.15 (s, 1H), 2.56 (s, 3H), 2.30 (s, 3H), 0.96 (s, 9H). HPLC (Kinetex2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5 min run): t_(R)(min)=4.06.

Example 772-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (79)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (79):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxy-1-methylpiperidin-4-yl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (79) was prepared by the method of Example 68 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 4-ethynyl-1-methylpiperidin-4-ol. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.77(d, J=9 Hz, 1H), 7.70 (br s, 1H), 7.58 (m, 3H), 7.41 (d, J=8 Hz, 1H),7.30 (m, 2H), 5.16 (s, 1H), 3.35 (m, 4H), 2.89 (s, 3H), 2.60 (s, 3H),2.15 (m, 4H), 0.98 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₁H₃₅ClNO₄: 520.2. found: 520.1.

Example 782-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (80)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (80):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (80) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 4-ethynyltetrahydro-2H-pyran-4-ol. ¹H-NMR: 400 MHz, (CD₃OD) δ:7.76 (d, J=8 Hz, 7.68 (s, 1H), 7.57 (m, 3H), 7.42 (d, J=9 Hz, 1H), 7.30(m, 2H), 5.16 (s, 1H), 3.85 (br m, 2H), 3.65 (br m, 2H), 2.60 (s, 3H),1.92 (br m, 2H), 1.77 (br m, 2H), 0.98 (s, 9H). HPLC (Kinetex 2.6u,50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 3.5 min run): t_(R) (min)=2.41.

Example 792-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-((1-methyl-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)aceticacid (81)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-((1-methyl-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)aceticacid (81):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-((1-methyl-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)aceticacid (81) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 5-ethynyl-1-methyl-1H-imidazole. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.80(br s, 1H), 7.87 (d, J=8 Hz, 1H), 7.76 (s, 1H), 7.58 (m, 5H), 7.48 (s,1H), 7.33 (d, J=8 Hz, 1H), 5.18 (s, 1H), 3.92 (s, 3H), 2.63 (s, 3H),0.98 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₈ClN₂O₃: 487.2.found: 487.2.

Example 802-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-ethyl-3-hydroxypent-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (82)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-ethyl-3-hydroxypent-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (82):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-ethyl-3-hydroxypent-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (82) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 3-ethylpent-1-yn-3-ol. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.74 (d, J=8Hz, 1H), 7.67 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.30 (m, 2H),5.17 (s, 1H), 2.59 (s, 3H), 1.69 (m, 4H), 1.01 (m, 6H), 0.98 (s, 9H).HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 3.5 min run):t_(R) (min)=2.64.

Example 812-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (83)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (83):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclohexyl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid (83) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 1-ethynylcyclohexanol. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.75 (d, J=8Hz, 1H), 7.68 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.31 (d, J=8Hz, 1H), 7.28 (s, 1H), 5.17 (s, 1H), 2.60 (s, 3H), 1.91 (m, 2H),1.57-1.71 (m, 8H), 0.98 (s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100%MeCN/H₂O+0.05% HOAc, 3.5 min run): t_(R) (min)=2.66.

Example 822-(7-((1-Aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (84)

Preparation of2-(7-((1-aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (84):2-(7-((1-Aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (84) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 1-ethynylcyclohexanamine. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.82 (d, J=8Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.47 (d, J=8 Hz, 1H), 7.37 (s, 1H),7.31 (d, J=8 Hz, 1H), 5.20 (s, 1H), 2.60 (s, 3H), 2.11 (m, 2H),1.63-1.85 (m, 8H), 0.99 (s, 9H). LCMS-ESI⁺ (m/z): [M—NH₂]⁺ calcd forC₃₁H₃₂ClO₃: 487.2. found: 487.2.

Example 832-(7-(3-Amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (85)

Preparation of2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (85):2-(7-(3-Amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (85) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 2-methylbut-3-yn-2-amine. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.81 (d, J=8Hz, 1H), 7.72 (s, 1H), 7.57 (m, 3H), 7.45 (d, J=8 Hz, 1H), 7.35 (s, 1H),7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.62 (s, 3H), 1.68 (s, 6H), 0.98 (s,9H). LCMS-ESI⁺ (m/z): [M—NH₂]⁺ calcd for C₂₈H₂₈ClO₃: 447.2. found:446.9.

Example 84(S)-2-((R)-7-(3-Amino-3-methylbut-1-ynyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (86)

Preparation of(S)-2-((R)-7-(3-amino-3-methylbut-1-ynyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (86):(S)-2-((R)-7-(3-Amino-3-methylbut-1-ynyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (86) (racemic with relative stereochemistry) was prepared by themethod of Example 67 from ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetateusing 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid. Theremainder of the sequence follows the method of Example 67 using2-methylbut-3-yn-2-amine was Step 7. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.72(d, J=6 Hz, 1H), 8.00 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.83 (m, 2H), 7.52(dd, J=8, 2 Hz, 1H), 7.46 (d, J=8 Hz, 1H), 7.07 (s, 1H), 5.21 (s, 1H),4.73 (m, 2H), 3.68 (t, J=6 Hz, 2H), 2.78 (s, 3H), 1.61 (s, 6H), 0.92 (s,9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₃H₃₅N₂O₄: 523.3. found: 523.1.

Example 852-(7-(3-Amino-3-methylbut-1-ynyl)-1-(chroman-6-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (87)

Preparation of2-(7-(3-amino-3-methylbut-1-ynyl)-1-(chroman-6-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (87):2-(7-(3-Amino-3-methylbut-1-ynyl)-1-(chroman-6-yl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (87) was prepared by the method of Example 67 from ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetateusing chroman-6-ylboronic acid. The remainder of the sequence followsthe method of Example 67 using 2-methylbut-3-yn-2-amine in Step 7.¹H-NMR: 400 MHz, (CD₃OD) δ: 7.77 (d, J=8 Hz, 1H), 7.66 (s, 1H), 7.48 (s,1H), 7.45 (m, 1H), 7.23 (m, 1H), 6.90 (m, 2H), 5.31 (s, 1H), 4.28 (t,J=5 Hz, 1H), 2.87 (m, 2H), 2.58 (s, 3H), 2.08 (m, 2H), 1.68 (s, 6H),0.99 (s, 9H). LCMS-ESI⁺ (m/z): [M—NH₂]⁺ calcd for C₃₁H₃₃O₄: 469.2.found: 469.2.

Example 862-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-phenylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (88)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-phenylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (88):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-phenylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (88) was prepared by the method of Example 67 from ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateusing 2-phenylbut-3-yn-2-ol. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.76 (d, J=8Hz, 1H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 2H), 7.57 (m, 3H), 7.46 (d, J=8Hz, 1H), 7.33 (m, 5H), 5.18 (s, 1H), 2.61 (s, 3H), 1.75 (s, 3H), 0.98(s, 9H). LCMS-ESI⁺ (m/z): [M—OH]⁺ calcd for C₃₃H₃₀ClO₃: 509.1. found:508.8.

Example 872-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbutyl)-3-methylnaphthalen-2-yl)aceticacid (89)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbutyl)-3-methylnaphthalen-2-yl)aceticacid (89): To a solution of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (8 mg, 0.017 mmol) in EtOH (1 mL) was added rhodium on alumina (2mg). The reaction was flushed with hydrogen gas and then stirred underand hydrogen atmosphere for 1 h. The reaction was filtered andconcentrated in vacuo to give 7 mg of the titled compound. ¹H-NMR: 400MHz, (CD₃OD) δ: 7.68 (d, J=8 Hz, 1H), 7.63 (m, 1H), 7.61 (s, 1H), 7.53(m, 2H), 7.30 (m, 2H), 7.05 (s, 1H), 5.12 (s, 1H), 2.65 (m, 2H), 2.59(s, 3H), 1.66 (m, 2H), 1.19 (s, 6H), 0.96 (s, 9H). HPLC (Kinetex 2.6u,50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 4.0 min run): t_(R) (min)=3.52.

Example 882-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopentylethyl)-3-methylnaphthalen-2-yl)aceticacid (90)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopentylethyl)-3-methylnaphthalen-2-yl)aceticacid (90):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopentylethyl)-3-methylnaphthalen-2-yl)aceticacid (90) was prepared using the procedure of Example 87 from2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(cyclopentylethynyl)-3-methylnaphthalen-2-yl)aceticacid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.69 (d, J=9 Hz, 1H), 7.63 (s, 1H),7.56 (m, 3H), 7.29 (m, 2H), 6.99 (s, 1H), 5.18 (s, 1H), 2.60 (m, 2H),2.58 (s, 3H), 1.71 (m, 3H), 1.52 (m, 6H), 1.07 (m, 2H), 0.98 (s, 9H).HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5.0 min run):t_(R) (min)=4.54.

Example 892-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-(1-hydroxycyclopentyl)ethyl)-methylnaphthalen-2-yl)aceticacid (91)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(2-(1-hydroxycyclopentyl)ethyl)-3-methylnaphthalen-2-yl)aceticacid (91):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-(1-hydroxycyclopentyl)ethyl)-3-methylnaphthalen-2-yl)aceticacid (91) was prepared using the procedure of Example 87 from2-tert-butoxy-2-(1-(4-chlorophenyl)-7-((1-hydroxycyclopentyl)ethynyl)-3-methylnaphthalen-2-yl)aceticacid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.78 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz,1H), 7.58 (s, 1H), 7.51 (m, 2H), 7.29 (m, 2H), 7.07 (s, 1H), 5.05 (s,1H), 2.70 (m, 2H), 2.62 (s, 3H), 1.75 (m, 4H), 1.61 (m, 6H), 0.94 (s,9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 4.0 minrun): t_(R) (min)=3.69.

Example 902-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopropylethyl)-3-methylnaphthalen-2-yl)aceticacid (92)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopropylethyl)-3-methylnaphthalen-2-yl)aceticacid (92):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(2-cyclopropylethyl)-3-methylnaphthalen-2-yl)aceticacid (92) was prepared using the procedure of Example 87 from2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(cyclopropylethynyl)-3-methylnaphthalen-2-yl)aceticacid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H),7.60 (m, 3H), 7.35 (m, 2H), 7.06 (s, 1H), 5.21 (s, 1H), 2.72 (t, J=7 Hz,2H), 2.62 (s, 3H), 1.48 (m, 2H), 0.94 (s, 9H), 0.65 (m, 1H), 0.37 (m,2H), 0.01 (m, 2H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05%HOAc, 5.0 min run): t_(R) (min)=4.02.

Example 912-tert-Butoxy-2-(1-(4-chlorophenyl)-7-ethyl-3-methylnaphthalen-2-yl)aceticacid (93)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-ethyl-3-methylnaphthalen-2-yl)aceticacid (93):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-ethyl-3-methylnaphthalen-2-yl)aceticacid (93) was prepared using the procedure of Example 87 from2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-vinylnaphthalen-2-yl)aceticacid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.74 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz,1H), 7.59 (s, 1H), 7.53 (m, 2H), 7.29 (m, 2H), 7.04 (s, 1H), 5.07 (s,1H), 2.60 (m, 5H), 1.15 (t, J=7 Hz, 3H), 0.94 (s, 9H). HPLC (Kinetex2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 4.0 min run): t_(R)(min)=3.81.

Example 922-tert-Butoxy-2-(1-(4-chlorophenyl)-7-isobutyl-3-methylnaphthalen-2-yl)aceticacid (94)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-isobutyl-3-methylnaphthalen-2-yl)aceticacid (94):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-isobutyl-3-methylnaphthalen-2-yl)aceticacid (94) was prepared using the procedure of Example 87 from2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-(2-methylprop-1-enyl)naphthalen-2-yl)aceticacid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.66 (m, 3H), 7.55 (m, 2H), 7.28 (m,2H), 6.97 (s, 1H), 5.13 (s, 1H), 2.59 (s, 3H), 2.44 (d, J=7 Hz, 2H),0.96 (s, 9H), 0.83 (m, 6H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100%MeCN/H₂O+0.05% HOAc, 4.0 min run): t_(R) (min)=3.03.

Example 932-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-(dimethylamino)-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (95)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-(dimethylamino)-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (95): To a solution of2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (12 mg, 0.026 mmol) in MeOH (1 mL) was added acetic acid (100 μL),formaldehyde (50 μL, 37% in water), and sodium triacetoxyborohydride (10mg). After 30 min, the reaction mixture was filtered and purified byreverse phase HPLC (MeCN/H₂O w/0.1% TFA) to give 4 mg of the titledcompound.

¹H-NMR: 400 MHz, (CD₃OD) δ: 7.85 (d, J=8 Hz, 1H), 7.74 (s, 1H), 7.57 (m,3H), 7.51 (d, J=8 Hz, 1H), 7.40 (s, 1H), 7.31 (d, J=8 Hz, 1H), 5.16 (s,1H), 2.97 (s, 6H), 2.62 (s, 3H), 1.75 (s, 6H), 0.98 (s, 9H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₀H₃₅ClNO₃: 492.2. found: 492.0.

Example 942-(7-(3-Acetamido-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (96)

Preparation of2-(7-(3-acetamido-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (96): To a solution of2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (12 mg, 0.026 mmol) in CH₂Cl₂ (1 mL) was added triethylamine (50 L)and acetic anhydride (10 μL) and trace DMAP. After 30 min, the reactionmixture was filtered and purified by reverse phase HPLC (MeCN/H₂O w/0.1%TFA) to give 10 mg of the titled compound. ¹H-NMR: 400 MHz, (CD₃OD) δ:7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.58 (m, 3H), 7.40 (d, J=9 Hz, 1H),7.32 (d, J=9 Hz, 1H), 7.27 (s, 1H), 5.16 (s, 1H), 2.60 (s, 3H), 1.90 (s,3H), 1.61 (s, 6H), 0.98 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₀H₃₃ClNO₄: 506.2. found: 506.0.

Example 952-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-(methoxycarbonylamino)-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (97)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-(methoxycarbonylamino)-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (97):2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-(methoxycarbonylamino)-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (97) was prepared by the method of Example 94 from2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid using methyl chloroformate. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.72 (d,J=8 Hz, 1H), 7.67 (s, 1H), 7.57 (m, 3H), 7.40 (d, J=8 Hz, 1H), 7.31 (d,J=9 Hz, 1H), 7.26 (s, 1H), 5.16 (s, 1H), 3.60 (s, 3H), 2.60 (s, 3H),1.58 (s, 6H), 0.98 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₀H₃₃ClNO₅: 522.2. found: 522.1.

Example 96(S)-2-(7-(3-Amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (98)

Preparation of(S)-2-(7-(3-amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (98):(S)-2-(7-(3-Amino-3-methylbut-1-ynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (98) was prepared by the method of Example 67 using the reductionmethod of Example 51, step 3, for (S)-ethyl2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBH₄ step, fromethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. Theremainder of the sequence follows the method of Example 67 using2-methylbut-3-yn-2-amine in Step 7. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.81 (d,J=8 Hz, 1H), 7.72 (s, 1H), 7.57 (m, 3H), 7.45 (d, J=8 Hz, 1H), 7.35 (s,1H), 7.30 (d, J=8 Hz, 1H), 5.16 (s, 1H), 2.62 (s, 3H), 1.68 (s, 6H),0.98 (s, 9H). LCMS-ESI⁺ (m/z): [M—NH₂]calcd for C₂₈H₂₈ClO₃: 447.2.found: 446.9.

Example 97(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (99)

Preparation of(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (99):(S)-2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (99) was prepared by the method of Example 67 using the reductionmethod of Example 51 step 3 for (S)-ethyl2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBH₄ step, fromethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. Theremainder of the sequence follows the method of Example 67 using2-methylbut-3-yn-2-ol in Step 7.1H-NMR: 400 MHz, (CD₃OD) δ: 7.73 (d, J=9Hz, 1H), 7.67 (s, 1H), 7.57 (m, 3H), 7.38 (d, J=9 Hz, 1H), 7.30 (d, J=9Hz, 1H), 7.26 (s, 1H), 5.16 (s, 1H), 2.60 (s, 3H), 1.51 (s, 6H), 0.98(s, 9H). HPLC (Kinetex 2.6u, 50×4.6 mm, 2-100% MeCN/H₂O+0.05% HOAc, 5min run): t_(R) (min)=3.40.

Example 98(S)-2-(7-((1-Aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (100)

Preparation of(S)-2-(7-((1-aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (100):(S)-2-(7-((1-Aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (100) was prepared by the method of Example 67 using the reductionmethod of Example 51 step 3 for (S)-ethyl2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBH₄ step, fromethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. Theremainder of the sequence follows the method of Example 67 using1-ethynylcyclohexanamine in Step 7. ¹H-NMR: 400 MHz, (CD₃OD) δ: 7.82 (d,J=8 Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.47 (d, J=8 Hz, 1H), 7.37 (s,1H), 7.31 (d, J=8 Hz, 1H), 5.20 (s, 1H), 2.60 (s, 3H), 2.11 (m, 2H),1.63-1.85 (m, 8H), 0.99 (s, 9H). LCMS-ESI (m/z): [M—NH₂]⁺ calcd forC₃₁H₃₂ClO₃: 487.2. found: 487.2.

Example 99(S)-2-tert-Butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (101)

Preparation of 1-(3-chloro-4-fluorophenyl)propan-2-one: To a solution of2-(3-chloro-4-fluorophenyl)acetic acid (18.46 g, 97.89 mmol) in aceticanhydride (463 mL) was added N-methylimidazole (3.9 mL) and the reactionmixture was stirred overnight at room temperature. The reaction mixturewas partitioned between ethyl acetate and saturated sodium bicarbonatesolution and organic layer was concentrated and purified by flash columnchromatography (silica gel, ethyl acetate/hexanes) to give a colorlessoil (14.5 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ 7.23 (dd, J=6.9, 2.1 Hz,1H), 7.14-7.00 (m, 2H), 3.66 (s, 2H), 2.19 (s, 3H).

Preparation of ethyl 4-(3-chloro-4-fluorophenyl)-3-methylbut-2-enoate:To a solution of triethylphosphonoacetate (25.3 mL, 126.2 mmol) inanhydrous tetrahydrofuran (250 mL) at 0° C. was added 60% sodium hydride(5.15 g, 126.2 mmol) and the resulting mixture stirred for 30 minutes.1-(3-chloro-4-fluorophenyl)propan-2-one (15.7 g, 84.13 mmol) intetrahydrofuran (10 mL) added and the reaction mixture was stirred for 2hours and quenched with saturated sodium bicarbonate solution. Themixture was extracted with ethyl acetate and organic layer wasconcentrated and purified by flash column chromatography (silica gel,ethyl acetate/hexanes) to give mixture of E/Z isomers (17.2 g, 80%). Eisomer: ¹H NMR (400 MHz, CDCl₃): δ 7.19 (dd, J=7.0, 2.1 Hz, 1H),7.12-6.97 (m, 2H), 5.64 (d, J=1.2 Hz, 1H), 4.13 (dq, J=14.4, 7.2 Hz,3H), 3.36 (s, 2H), 2.03 (s, 3H), 1.26 (dd, J=15.9, 7.2 Hz, 3H); Zisomer: ¹H NMR (400 MHz, CDCl₃): δ 7.28 (dd, J=7.1, 2.1 Hz, 1H),7.15-6.98 (m, 2H), 5.79 (s, 1H), 4.17 (dq, J=14.3, 7.1 Hz, 2H), 3.37 (s,2H), 1.79 (s, 3H), 1.29 (dd, J=15.1, 7.2 Hz, 3H).

Preparation of 6-chloro-7-fluoro-3-methylnaphthalen-1-ol: A solution ofethyl 4-(3-chloro-4-fluorophenyl)-3-methylbut-2-enoate (9.7 g, 37.8mmol) in concentrated sulfuric acid (40 mL) was stirred at 50° C.overnight. The reaction mixture was poured onto ice and diluted withwater and extracted with ethyl acetate. The organic layer wasconcentrated and purified by flash column chromatography (silica gel,ethyl acetate/hexanes) to give a pale yellow solid (1.57 g). ¹H-NMR: 400MHz, (CDCl₃) δ: 7.83 (d, J=10.4 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.11(s, 1H), 6.67 (s, 1H), 2.42 (s, 3H).

Preparation of ethyl2-(6-chloro-7-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate:To a mixture of 6-chloro-7-fluoro-3-methylnaphthalen-1-ol (2.24 g, 13.78mmol) in anhydrous dichloromethane (100 mL) at −40° C. was added a 1 Mtitanium(IV) chloride solution in dichloromethane (13.78 mL, 13.78 mmol)and stirred for 45 min. Ethyl glyoxylate (1.69 g, 16.54 mmol) dissolvedin dichloromethane (5 mL) was added over 15 minutes and stirred for 1hour at −40° C. The reaction was quenched by the addition of Rochelle'ssalt solution and stirred at room temperature for 2.5 hours. Theresulting mixture was washed with water and aqueous layer back-extractedwith dichloromethane (2×). The combined organic layer was dried (MgSO₄),filtered, concentrated and purified by flash column chromatography(silica gel, 5 to 30% ethyl acetate/hexanes) to give an off-white solid(2.53 g). ¹H-NMR: 400 MHz, (CDCl₃) δ: 8.48 (s, 1H), 7.89 (d, J=10.5 Hz,1H), 7.70 (d, J=7.2 Hz, 1H), 7.11 (s, 1H), 5.67 (s, 1H), 4.30 (dq,J=10.8, 7.1 Hz, 1H), 4.15 (dq, J=10.8, 7.1 Hz, 1H), 3.61 (s, 1H), 2.52(s, 3H), 1.20 (t, J=7.1 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₁₅H₁₃ClFO₄: 311.7. Found: 311.0.

Preparation of ethyl2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate:To a solution of ethyl2-(6-chloro-7-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate(4.13 g, 13.22 mmol) in anhydrous dichloromethane (120 mL) at 0° C. wasadded imidazole (1.215 g, 17.85 mmol), followed by chlorotriethylsilane(2.55 mL, 15.2 mmol). The cloudy reaction mixture was stirred for 1.5hours, quenched with water and diluted with dichloromethane. The mixturewas washed with 1 N HCl solution/brine and organic layer dried (MgSO₄),filtered, concentrated to give an orange oil that used in next stepwithout further purification.

The above residue was dissolved in anhydrous dichloromethane (130 mL)containing triethylamine (2.21 mL, 15.86 mmol) and cooled in a dryice/acetone bath. Trifluoromethanesulfonic anhydride (2.45 mL, 14.54mmol) was added dropwise over 20 minutes and stirred for 1 hour. Thereaction was quenched with brine and stirred for 15 minutes at roomtemperature. The mixture was diluted with dichloromethane, washed with 1N HCl solution, saturated sodium bicarbonate solution/brine and dried(MgSO₄), filtered, concentrated to give an orange oil that used in nextstep without further purification.

The above residue was dissolved in tetrahydrofuran (100 mL) and 48%hydrofluoric acid (16.77 mL, 462.7 mmol) was added. The reaction mixturewas stirred overnight at room temperature and quenched with solid sodiumbicarbonate and stirred for 30 minutes. Water and saturated sodiumbicarbonate were added and the mixture was extracted with ethyl acetate(2×). The combined organic layer was dried (MgSO₄), filtered,concentrated and purified by flash column chromatography (silica gel, 5to 30% ethyl acetate/hexanes) to give an off-white solid (4.89 g).¹H-NMR: 400 MHz, (CDCl₃) δ: 7.87 (d, J=7.1 Hz, 1H), 7.76 (d, J=10.1 Hz,1H), 7.59 (s, 1H), 5.76 (d, J=2.0 Hz, 1H), 4.36-4.18 (m, 2H), 3.42 (d,J=2.4 Hz, 1H), 2.48 (s, 3H), 1.20 (t, J=7.1 Hz, 3H).

Preparation of ethyl2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)-2-oxoacetate:To a solution of ethyl2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate(4.89 g, 10.99 mmol) in anhydrous dichloromethane (100 mL) at 0° C. wasadded Dess-Martin periodinane (5.59 g, 13.18 mmol) portion-wise over 5minutes. The reaction mixture was stirred at 0° C. for 1 hour andquenched with sodium thiosulfate solution and saturated sodiumbicarbonate solution and stirred for 30 minutes. The mixture was dilutedwith ethyl ether and washed with saturated sodium bicarbonate solution(3×), brine and dried (MgSO₄), filtered, concentrated to give a yellowoil with a white precipitate. The mixture was suspended in diethylether, washed with brine, dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, 0 to 10% ethylacetate/hexanes) to give an off-white solid (4.60 g). ¹H NMR (400 MHz,CDCl₃) δ: 7.93 (d, J=7.0 Hz, 1H), 7.78 (d, J=9.6 Hz, 1H), 7.67 (s, 1H),4.41 (q, J=7.1 Hz, 2H), 2.47 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).

Preparation of (S)-ethyl2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate:To a solution of ethyl2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate(4.60 g, 10.79 mmol) and (R)-2-methyl-CBS-oxazaborolidine (0.598 g, 2.16mmol) in anhydrous toluene at −40° C. was added a solution ofcatecholborane (1.55 mL, 14.67 mmol) in toluene (10 mL) over 40 minutes.The reaction mixture was stirred for 1 hour and quenched with sodiumcarbonate solution, diluted with ethyl acetate and stirred vigorouslyfor 20 minutes at −20° C., then at room temperature for 45 minutes. Theaqueous layer was removed and the organic layer was washed with sodiumcarbonate solution (4×), saturated ammonium chloride solution, dried(MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give anoff-white solid (4.44 g). ¹H NMR (400 MHz, CDCl₃) δ: 7.87 (d, J=7.1 Hz,1H), 7.76 (d, J=10.0 Hz, 1H), 7.59 (s, 1H), 5.76 (d, J=1.7 Hz, 1H),4.38-4.17 (m, 2H), 3.43 (d, J=2.3 Hz, 1H), 2.48 (s, 3H), 1.20 (t, J=7.1Hz, 3H). The enantiomeric excess was determined by chiral columnanalysis (Chiralpak AD-H, heptane:ethanol (80:20)) to be 95%.

Preparation of (S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:To a solution of (S)-ethyl2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate(4.44 g, 9.99 mmol) in tert-butylacetate (100 mL) was added 70%perchloric acid (1.20 mL, 19.98 mmol). The reaction mixture was stirredfor 2.5 hours and quenched with solid sodium bicarbonate and stirred for45 minutes. Water and solid sodium bicarbonate were carefully added andstirred for another 15 minutes. The mixture was diluted with ethylacetate, washed with saturated bicarbonate solution (2×), brine, dried(MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give anpale orange oil (4.26 g). ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (d, J=7.2 Hz,4H), 7.74 (d, J=10.2 Hz, 4H), 7.58 (s, 4H), 7.26 (s, 3H), 5.69 (s, 4H),4.26-4.08 (m, 9H), 2.53 (s, 12H), 1.20 (s, 34H), 1.17 (t, J=7.1 Hz,13H).

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(110 mg, 0.199 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronicacid, HCl salt (55 mg, 0.220 mmol), PdCl₂(dppf) (16 mg, 0.02 mmol),cesium fluoride (133 mg, 0.876 mmol) and flushed with nitrogen.Dimethoxyethane (1.0 mL, distilled from Na/benzophenone) was added andmixture sparged with nitrogen for 10 minutes and then heated inmicrowave at 110° C. for 1 hour. The reaction mixture was diluted withethyl acetate and washed with brine, dried (MgSO₄), filtered,concentrated and purified by flash column chromatography (silica gel, 0to 20% ethyl acetate/hexanes) to give (S)-ethyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(9.7 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.49 (d, J=4.4 Hz, 1H), 7.97 (d,J=7.5 Hz, 1H), 7.74 (s, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.27 (d, J=4.4 Hz,1H), 7.14 (d, J=7.9 Hz, 1H), 6.66 (d, J=11.5 Hz, 1H), 5.13 (s, 1H), 4.56(dd, J=9.9, 5.9 Hz, 2H), 3.96 (dd, J=10.8, 7.1 Hz, 1H), 3.76 (dd,J=10.7, 7.1 Hz, 1H), 3.38 (t, J=5.8 Hz, 2H), 2.74 (s, 3H), 0.98-0.85 (m,12H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₀ClFNO₄: 523.0. Found:522.1, 524.1.

The other atropisomer, (S)-ethyl2-tert-butoxy-2-((S)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate,was also isolated (16.4 mg). ¹H NMR (400 MHz, CD₃OD): δ 8.47 (d, J=4.4Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.70 (s, 1H),7.25 (d, J=4.4 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.56 (d, J=11.4 Hz, 1H),5.15 (s, 2H), 4.52 (t, J=5.4 Hz, 2H), 4.22-4.04 (m, 2H), 3.37 (t, J=5.8Hz, 2H), 2.61 (s, 3H), 1.20 (t, J=5.9 Hz, 3H), 0.70 (s, 9H). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₀H₃₀ClFNO₄: 523.0. Found: 522.1, 524.1.

Preparation of(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (101): A solution of (S)-ethyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(9.7 mg, 0.186 mmol) and 5 M sodium hydroxide (74 μL, 0.372 mmol) intetrahydrofuran (1.0 mL) and methanol (0.2 mL) was heated at 50° C.overnight. The reaction mixture was diluted with ethyl acetate andwashed with brine. The aqueous layer was back-extracted with ethylacetate and the combined organic layer was dried (MgSO₄), filtered,concentrated and purified by reverse phase HPLC (Gemini, 5 to 100%ACN/H₂O+0.1% TFA). Product lyophilized to give a yellow powder (6.7 mg).¹H-NMR: 400 MHz, (CD₃OD): δ 8.69 (d, J=5.2 Hz, 1H), 8.12 (d, J=7.6 Hz,1H), 7.96 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.45(d, J=8.0 Hz, 1H), 6.73 (d, J=11.2 Hz, 1H), 5.21 (s, 1H), 4.75-4.70 (m,2H), 3.66 (t, J=6 Hz, 2H), 2.76 (s, 3H) 0.92 (s, 9H). ¹⁹F-NMR: 377 MHz,(CD₃OD) δ: −77.7 (s, 3F), −119.2 (dd, J=10.6, 7.9 Hz, 1F). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₈H₂₆ClFNO₄: 494.95. Found: 494.4, 496.1. Theother atropisomer,(S)-2-tert-butoxy-2-((S)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid, was prepared in a similar manner. ¹H NMR (400 MHz, CD₃OD): δ 8.59(d, J=5.3 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.88(s, 1H), 7.63 (d, J=5.2 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 6.68 (d, J=11.2Hz, 1H), 5.20 (s, 1H), 4.68 (t, J=6.0 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H),2.71 (s, 3H), 0.85 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.7 (s, 3F),−120.0 (br s, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₆C1FNO₄:494.95. Found: 494.4, 496.1.

Example 100(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-6-isopropyl-3-methylnaphthalen-2-yl)aceticacid (102)

Preparation of (S)-ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-6-(prop-1-en-2-yl)-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(184.2 mg, 0.368 mmol), potassium isopropenyltrifluoroborate (60 mg,0.405 mmol), BrettPhos Palladacycle (41 mg, 0.0552 mmol), cesiumfluoride (623 mg, 0.405 mmol) and flushed with nitrogen. Dimethoxyethane(1.0 mL, distilled from Na/benzophenone) was added and mixture spargedwith nitrogen for 10 minutes and then heated in microwave at 120° C. for1.5 hour. The reaction mixture was diluted with ethyl acetate and washedwith water, brine, dried (MgSO₄), filtered, concentrated and purified byflash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes)to give a colorless oil (60 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d,J=7.1 Hz, 13H), 7.71 (d, J=7.5 Hz, 1H), 5.70 (s, 1H), 5.35 (s, 1H), 5.32(s, 1H), 4.18 (dt, J=19.3, 11.4 Hz, 2H), 2.53 (s, 3H), 2.21 (s, 3H),1.24-1.12 (m, 12H).

Preparation of(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(prop-1-en-2-yl)naphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-6-(prop-1-en-2-yl)-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(92.3 mg, 0.182 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronicacid, HCl salt (50 mg, 0.200 mmol), Sphos Palladacycle (18.4 mg, 0.0273mmol), cesium fluoride (122 mg, 0.801 mmol) and flushed with nitrogen.Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added andmixture sparged with nitrogen for 10 minutes and then heated inmicrowave at 120° C. for 1.5 hour. The reaction mixture was diluted withethyl acetate and washed with brine. Aqueous layer back-extracted andcombined organic layer dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, 0 to 20% ethylacetate/hexanes) to give impure (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(prop-1-en-2-yl)naphthalen-2-yl)acetate(10 mg). Repurified by reverse phase HPLC (Gemini, 5 to 100%ACN/H₂O+0.1% TFA) and lyophilized to give an impure yellow powder (4.3mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₃H₃₅FNO₄: 528.6. Found: 528.1,529.1.

The other atropisomer, (S)-ethyl2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(prop-1-en-2-yl)naphthalen-2-yl)acetate,was also isolated (4.3 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₃H₃₅FNO₄: 528.6. Found: 528.1, 529.1

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-6-isopropyl-3-methylnaphthalen-2-yl)acetate:A mixture of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(prop-1-en-2-yl)naphthalen-2-yl)acetate(4.3 mg, 0.007 mmol) and 10% Palladium/carbon (5.0 mg) in ethanol (1.5mL) was stirred under a hydrogen atmosphere (1 atm) for 2 hours. Thereaction mixture was filtered through a pad of Celite and concentratedto give a film that was used in the next step without furtherpurification (4.2 mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₃H₃₇FNO₄:530.6. Found: 530.2.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-6-isopropyl-3-methylnaphthalen-2-yl)aceticacid (102): A solution of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-6-isopropyl-3-methylnaphthalen-2-yl)acetate(4.2 mg, 0.007 mmol) and 5 M sodium hydroxide (31 μL, 0.16 mmol) intetrahydrofuran (1.0 mL) and methanol (0.1 mL) was heated at 50° C.overnight. The reaction mixture was acidified with acetic acid,concentrated, dissolved in DMF and purified by reverse phase HPLC(Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Product lyophilized to give ayellow powder (2.6 mg).

¹H-NMR: 400 MHz, (CD₃OD) δ: 8.67 (d, J=5.6 Hz, 1H), 7.94 (s, 1H), 7.84(d, J=7.6 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.43(d, J=8.0 Hz, 1H), 6.47 (d, J=12.4 Hz, 1H), 5.21 (s, 1H), 4.75-4.70 (m,2H), 3.66 (t, J=6 Hz, 2H), 3.3-2.2 (m, 1H), 2.75 (s, 3H), 1.33 (d, J=8.4Hz, 3H), 1.31 (d, J=8.8 Hz, 3H), 0.92 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD)δ: −77.6 (s, 3F), −121.4 (dd, J=10.6, 7.9 Hz, 1F). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₁H₃₃FNO₄: 502.69. Found: 502.1 (M+H⁺).

Example 101(S)-2-tert-Butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (103)

Preparation of (S)-ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(213.6 mg, 0.426 mmol), tributyl(vinyl)tin (0.137 mL, 0.469 mmol),BrettPhos Palladacycle (47 mg, 0.0639 mmol) and flushed with nitrogen.DMF (2.0 mL) and sodium carbonate (5.0 mg, 0.0639 mmol) were added andheated in microwave at 120° C. for 1.5 hour. The reaction mixture wasdiluted with ethyl acetate and washed with 5% lithium chloride solution(2×), brine, dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) togive a colorless oil (149.5 mg). ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d,J=5.1 Hz, 1H), 7.62 (d, 1H), 6.95 (dd, J=17.7, 11.3 Hz, 1H), 6.00 (d,J=17.7 Hz, 1H), 5.52 (d, J=11.3 Hz, 1H), 4.33-4.03 (m, 2H), 2.53 (s,3H), 1.20 (s, 9H), 1.17 (t, J=7.1 Hz, 3H).

Preparation of(S)-ethyl2-tert-butoxy-2-(7-fluoro-6-formyl-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:A 3-neck round-bottom flask was charged with (S)-ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate(95 mg, 0.193 mmol), methanol (1 mL) and dichloromethane (1 mL) andcooled to −78° C. Ozone was bubbled into the reaction mixture until bluecolor persisted (2 minutes). The reaction was sparged with oxygen untilblue color faded and quenched with methyl sulfide (0.06 mL, 0.828 mmol).The mixture was stirred at room temperature for 1 h, concentrated andpurified by flash column chromatography (silica gel, 0 to 10% ethylacetate/hexanes) to give a colorless oil (74 mg). ¹H NMR (400 MHz,CDCl₃) δ 10.45 (s, 1H), 8.37 (d, J=6.8 Hz, 1H), 7.80 (s, 1H), 7.75 (d,J=11.7 Hz, 1H), 5.72 (s, 1H), 4.39-4.00 (m, 2H), 2.56 (s, 3H), 1.20 (s,9H), 1.17 (t, J=7.1 Hz, 3H).

Preparation of (S)-ethyl2-tert-butoxy-2-(6-(difluoromethyl)-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:To a solution of S)-ethyl2-tert-butoxy-2-(7-fluoro-6-formyl-3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)acetate(37.3 mg, 0.075 mmol) in dichloromethane (0.5 mL) at 0° C. was addedDeoxo-Fluor (28 μL, 0.151 mmol). The reaction mixture was stirred for2.5 hours at 0° C., then loaded directly onto a silica gel column andpurified by flash column chromatography (silica gel, 0 to 10% ethylacetate/hexanes) to give a colorless oil (32.7 mg). ¹H NMR (400 MHz,CDCl₃) δ 8.06 (d, J=6.8 Hz, 1H), 7.75 (s, 1H), 7.73 (d, J=10.7 Hz, 1H),6.99 (t, J=54.8 Hz, 1H), 5.72 (s, 1H), 4.36-3.93 (m, 2H), 2.56 (s, 3H),1.20 (s, 9H), 1.17 (t, J=7.1 Hz, 3H).

Preparation of(S)-ethyl2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-(difluoromethyl)-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(53.6 mg, 0.104 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronicacid, HCl salt (31.3 mg, 0.125 mmol), Sphos Palladacycle (10.5 mg,0.0156 mmol), cesium fluoride (69.5 mg, 0.458 mmol) and flushed withnitrogen. Dimethoxyethane (1.0 mL, distilled from Na/benzophenone) wasadded and mixture sparged with nitrogen for 10 minutes and then heatedin microwave at 120° C. for 1.5 hour. The reaction mixture was dilutedwith ethyl acetate and washed with brine. Aqueous layer back-extractedand combined organic layer dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, 0 to 20% ethylacetate/hexanes) to give (S)-ethyl2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(10 mg). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₁H₃₁F₃NO₄: 538.6. found:538.1.

The other atropisomer, (S)-ethyl2-tert-butoxy-2-((S)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate,was also isolated (12.0 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₁H₃₁F3NO₄: 538.6. found: 538.1.

Preparation of(S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (103): A solution of (S)-ethyl2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(10.0 mg, 0.0186 mmol) and 5 M sodium hydroxide (74 L, 0.372 mmol) intetrahydrofuran (1.0 mL) and methanol (0.1 mL) was heated at 50° C.overnight. The reaction mixture was re-suspended in methanol andconcentrated to −1 mL. DMF (0.3 mL) was added and concentrated to ˜0.3mL. Acetic acid was added, further diluted with DMF and purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Productlyophilized to give a yellow powder (9.8 mg).

¹H NMR (400 MHz, CD₃OD) δ 8.70 (d, J=5.7 Hz, 1H), 8.24 (d, J=7.2 Hz,1H), 8.10 (s, 1H), 7.82 (t, J=7.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 1H), 7.04(t, J=54.5 Hz, 1H), 6.71 (d, J=12.2 Hz, 1H), 5.24 (s, 1H), 4.81-4.64 (m,2H), 3.67 (t, J=6.0 Hz, 2H), 2.79 (s, 3H), 0.93 (s, 9H). ¹⁹F NMR (377MHz, CD₃OD) δ−77.77 (s), −114.82−−118.07 (m), −123.29 (m). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₉H₂₇F3NO₄: 510.5. found: 510.1.

Example 102(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (104)

Preparation of (S)-ethyl2-tert-butoxy-2-(6-ethyl-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:A mixture of (S)-ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate(23 mg, 0.050 mmol) and 10% Palladium on carbon (5 mg) in ethanol (2.0mL) was stirred under a hydrogen atmosphere for 4 hours, then filteredthrough a pad of Celite. Filtrate was concentrated to give a thin film(23 mg) that was used in the next step without further purification.

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-ethyl-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(23.4 mg, 0.0473 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronicacid, HCl salt (14.3 mg, 0.568 mmol), Sphos Palladacycle (4.8 mg, 0.0071mmol), cesium fluoride (31.6 mg, 0.208 mmol) and flushed with nitrogen.Dimethoxyethane (1.0 mL, distilled from Na/benzophenone) was added andmixture sparged with nitrogen for 10 minutes and then heated inmicrowave at 120° C. for 1.5 hour. The reaction mixture was diluted withethyl acetate and washed with brine. Aqueous layer back-extracted andcombined organic layer dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, 0 to 20% ethylacetate/hexanes) to give (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)acetate(1.7 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₃₅FNO₄: 516.6. found:516.1. The other atropisomer, (S)-ethyl2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)acetate,was also isolated (2.6 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₂H₃₅FNO₄: 516.6. found: 516.1.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (104): A solution of(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-7-fluoro-3-methylnaphthalen-2-yl)acetate(1.7 mg, 0.005 mmol) and 5 M sodium hydroxide (21 μL, 0.101 mmol) intetrahydrofuran (1.0 mL) and methanol (0.1 mL) was heated at 50° C.overnight. The reaction mixture was acidified with acetic acid,concentrated, dissolved in DMF and purified by reverse phase HPLC(Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Product lyophilized to give ayellow powder (1.3 mg). ¹H NMR (400 MHz, CD₃OD) δ 8.68 (d, J=5.6 Hz,1H), 7.93 (s, 1H), 7.87-7.77 (m, J=7.0 Hz, 3H), 7.46 (d, J=8.1 Hz, 1H),6.49 (d, J=12.1 Hz, 1H), 5.21 (s, 1H), 4.73 (d, J=6.3 Hz, 2H), 3.67 (t,J=6.0 Hz, 2H), 2.83-2.72 (m, 6H), 1.28 (t, J=7.5 Hz, 4H), 0.92 (s, 9H).¹⁹F NMR (377 MHz, CD₃OD) δ−77.86 (s), −121.37 (d, J=7.9 Hz). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₀H₃₁FNO₄: 488.6. found: 488.1.

Example 103(S)-2-tert-Butoxy-2-((R)-6-cyclopropyl-1-(2,3-dihydropyrano[4,3,2de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (105)

Preparation of (S)-ethyl2-tert-butoxy-2-(6-cyclopropyl-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(122.5 mg, 0.245 mmol), cyclopropylboronic acid (23 mg, 0.269 mmol),BrettPhos Palladacycle (27 mg, 0.0368 mmol), cesium fluoride (164 mg,1.08 mmol) and flushed with nitrogen.

Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added andmixture sparged with nitrogen for 15 minutes and then heated inmicrowave at 120° C. for 1.5 hour. The reaction mixture was diluted withethyl acetate and washed with brine. Aqueous layer back-extracted withethyl acetate and the combined organic layer was dried (MgSO₄),filtered, concentrated and purified by flash column chromatography(silica gel, 0 to 10% ethyl acetate/hexanes) to give an impure colorlessoil (83.1 mg). Analytical HPLC (Gemini, 2-98% ACN/H₂O+0.05% TFA): t_(R)(min)=5.53.

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-6-cyclopropyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-cyclopropyl-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(83.1 mg, 0.164 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronicacid, HCl salt (45.4 mg, 0.180 mmol), Sphos Palladacycle (16.5 mg,0.0246 mmol), cesium fluoride (110 mg, 0.722 mmol) and flushed withnitrogen. Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) wasadded and mixture sparged with nitrogen for 15 minutes and then heatedin microwave at 120° C. for 1.5 hour. The reaction mixture was dilutedwith ethyl acetate and washed with brine. Aqueous layer back-extractedand combined organic layer dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, 0 to 30% ethylacetate/hexanes) to give (S)-ethyl2-tert-butoxy-2-((R)-6-cyclopropyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(2.2 mg).

LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₃H₃₅FNO₄: 528.6. Found: 528.1,529.1. The other atropisomer, (S)-ethyl2-tert-butoxy-2-((S)-6-cyclopropyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate,was also isolated (2.8 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₃H₃₄FNO₄: 528.6; Found: 528.1, 529.1

Preparation of(S)-2-tert-butoxy-2-((R)-6-cyclopropyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (105): A solution of (S)-ethyl2-tert-butoxy-2-((R)-6-cyclopropyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(2.2 mg, 0.0042 mmol) and 5 M sodium hydroxide (171 μL, 0.083 mmol) intetrahydrofuran (0.5 mL) and methanol (0.1 mL) was heated at 45° C.overnight. The reaction mixture was concentrated, acidified with aceticacid, diluted in DMF and purified by reverse phase HPLC (Gemini, 5 to100% ACN/H₂O+0.1% TFA). Product lyophilized to give a yellow powder (2.2mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.67 (d, J=5.6 Hz, 1H), 7.89 (s, 1H),7.82-7.78 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.47(d, J=12.4 Hz, 1H), 5.20 (s, 1H), 4.76-4.49 (m, 2H), 3.66 (t, J=6 Hz,2H), 2.73 (s, 3H), 2.15-2.10 (m, 1H), 1.04 (d, J=8.4 Hz, 2H), 0.92 (s,9H), 0.86-0.83 (m, 2H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.7 (s, 3F),−121.8 (dd, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₁H₃₁FNO₄: 500.6.Found: 500.1.

Example 104(S)-2-tert-Butoxy-2-((R)-6-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (106A) and(S)-2-tert-Butoxy-2-((R)-6-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (106B)

Preparation of (S)-ethyl2-tert-butoxy-2-(6-cyano-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(180 mg, 0.359 mmol), zinc(II) cyanide (25 mg, 0.215 mmol), BrettPhosPalladacycle (26 mg, 0.0359 mmol), sodium bicarbonate (3 mg, 0.0359mmol). DMF (1.5 mL) was added and mixture was heated in microwave at110° C. for 1.0 hour. The reaction mixture was diluted with ethylacetate and washed with 5% lithium chloride solution (2×), brine, dried(MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give acolorless oil (129 mg). Analytical HPLC (Gemini, 2-98% ACN/H₂O+0.05%TFA): t_(R) (min)=5.01.

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-6-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-cyano-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(129 mg, 0.262 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronicacid, HCl salt (72.6 mg, 0.289 mmol), Sphos Palladacycle (26 mg, 0.0393mmol), cesium fluoride (175 mg, 1.15 mmol) and flushed with nitrogen.Dimethoxyethane (1.5 mL, distilled from Na/benzophenone) was added andmixture sparged with nitrogen for 15 minutes and then heated inmicrowave at 120° C. for 1.5 hour. The reaction mixture was diluted withethyl acetate and washed with brine. Aqueous layer back-extracted andcombined organic layer dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, 0 to 30% ethylacetate/hexanes) to give impure (S)-ethyl2-tert-butoxy-2-((R)-6-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(36.6 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₁H₃₀FN₂O₄: 513.6. Found:513.1. The other atropisomer, (S)-ethyl2-tert-butoxy-2-((S)-6-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate,was also isolated (36.8 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₁H₃₀FN₂O₄: 513.6. Found: 513.1.

Preparation of(S)-2-tert-butoxy-2-((R)-6-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (106A): A solution of (S)-ethyl2-tert-butoxy-2-((R)-6-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(36.8 mg, 0.0718 mmol) and 5 M sodium hydroxide (290 μL, 1.44 mmol) intetrahydrofuran (1.5 mL) and methanol (0.3 mL) was heated at 35° C.overnight. The reaction mixture was concentrated, acidified with aceticacid, diluted in DMF and purified by reverse phase HPLC (Gemini, 5 to100% ACN/H₂O+0.1% TFA). Product lyophilized to give a yellow powder(26.9 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.70 (d, J=5.6 Hz, 1H), 8.53 (d,J=6.8 Hz, 1H), 8.11 (s, 1H), 7.82-7.75 (m, 2H), 7.44 (d, J=8.0 Hz, 1H),6.83 (d, J=11.2 Hz, 1H), 5.24 (s, 1H), 4.76-4.68 (m, 2H), 3.66 (t, J=6Hz, 2H), 2.79 (s, 3H), 0.92 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.8(s, 3F), −115.5 (br s, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₆FN₂O₄: 485.5. Found: 485.1. Aside-product,(S)-2-tert-butoxy-2-((R)-6-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (106B), was also isolated (2.8 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ:8.70 (d, J=5.6 Hz, 1H), 8.44 (d, J=7.2 Hz, 1H), 8.09 (s, 1H), 7.82-7.80(m, 2H), 7.44 (d, J=8.0 Hz, 1H), 6.68 (d, J=13.2 Hz, 1H), 5.24 (s, 1H),4.76-4.70 (m, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.78 (s, 3H), 0.93 (s, 9H).¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.7 (s, 3F), −118.4 (br s, 1F). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₉H₂₈FN₂O₅: 503.5. Found: 503.1.

Example 105(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)aceticacid (107)

Preparation of (S)-ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-6-(methylcarbamoyl)-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(131.8 mg, 0.263 mmol), 2 M methylamine in THF (0.66 mL, 1.32 mmol),molybdenum hexacarbonyl (0.069 g, 0.263 mmol), BrettPhos Palladacycle(29 mg, 0.0395 mmol), and triethylamine (0.128 mL, 0.921 mmol). Toluene(1.5 mL) was added and mixture was heated in microwave at 140° C. for1.5 hour. The reaction mixture was diluted with ethyl acetate, washedbrine, dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 50% ethyl acetate/hexanes) togive an off-white solid (19.2 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₂H₂₆F4NO₇S: 524.5. Found: 524.0.

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-6-(methylcarbamoyl)-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(19.2 mg, 0.0367 mmol), 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronicacid, HCl salt (11.1 mg, 0.044 mmol), Sphos Palladacycle (3.7 mg, 0.0055mmol), cesium fluoride (25 mg, 0.161 mmol) and flushed with nitrogen.Dimethoxyethane (0.5 mL, distilled from Na/benzophenone) was added andmixture sparged with nitrogen for 10 minutes and then heated inmicrowave at 120° C. for 1.5 hour. The reaction mixture was diluted withethyl acetate and washed with brine. Aqueous layer back-extracted andcombined organic layer dried (MgSO₄), filtered, concentrated andpurified by flash column chromatography (silica gel, 30 to 80% ethylacetate/hexanes) to give (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)acetate(6.6 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₃₄FN₂O₅: 545.6. Found:545.1.

The other atropisomer, (S)-ethyl2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)acetate,was also isolated (7.5 mg). LCMS-ESI (m/z): [M+H]⁺ calcd forC₃₂H₃₄FN₂O₅: 545.6. Found: 545.1.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)aceticacid (107): A solution of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-6-(methylcarbamoyl)naphthalen-2-yl)acetate(6.6 mg, 0.012 mmol) and 5 M lithium hydroxide (48 μL, 0.242 mmol) intetrahydrofuran (1.0 mL) and methanol (0.3 mL) was heated at 55° C. for3 hours, then overnight at 48° C. Additional 5 M lithium hydroxidesolution (60 μL) was added and the reaction mixture stirred for 2 hoursat 60° C. The reaction mixture was acidified with acetic acid,concentrated, diluted in DMF and purified by reverse phase HPLC (Gemini,5 to 100% ACN/H₂O+0.1% TFA). Product lyophilized to give a yellow powder(5.0 mg). ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.70 (d, J=5.6 Hz, 1H), 8.35 (d,J=7.2 Hz, 1H), 8.07 (s, 1H), 7.82-7.80 (m, 2H), 7.44 (d, J=8.4 Hz, 1H),6.66 (d, J=12.8 Hz, 1H), 5.24 (s, 1H), 4.76-4.70 (m, 2H), 3.66 (t, J=6Hz, 2H), 2.94 (s, 3H), 2.78 (s, 3H), 0.92 (s, 9H).

¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.6 (s, 3F), −115.5 (dd, J=12.4, 7.16 Hz,1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₀FN₂O₅: 517.6. Found: 517.1.

Example 106(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (108)

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (108):(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (108) was prepared in a similar manner as(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 99 except starting with1-(3,4-difluorophenyl)propan-2-one instead of1-(3-chloro-4-fluorophenyl)propan-2-one.

¹H-NMR: 400 MHz, (CD₃OD) δ: 8.69 (d, J=5.6 Hz, 1H), 7.96 (s, 1H),7.83-7.78 (m, 3H), 7.45 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.74(d, J=8.0 Hz, 1H), 5.20 (s, 1H), 4.75-4.70 (m, 2H), 3.66 (t, J=5.6 Hz,2H), 2.76 (s, 3H) 0.92 (s, 9H).

¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.9 (s, 3F), −138.8—138.9 (m, 1F),−139.8—139.9 (m, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₆F₂NO₄:478.5. Found: 478.1. The other atropisomer,(S)-2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid, was prepared in a similar manner. ¹H NMR (400 MHz, CD₃OD) δ 8.60(d, J=5.4 Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.89 (s, 1H), 7.77 (dd,J=11.1, 8.2 Hz, 1H), 7.66 (d, J=5.4 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H),6.71 (dd, J=12.3, 7.9 Hz, 1H), 5.19 (s, 1H), 4.69 (t, J=6.0 Hz, 2H),3.60 (t, J=6.0 Hz, 2H), 2.71 (s, 3H), 0.86 (s, 9H). ¹⁹F NMR (377 MHz,CD₃OD) δ−78.04 (s), −139.49 (s), −140.31 (s). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₈H₂₆F₂NO₄: 478.5; Found: 478.1.

Example 107(R)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (109)

Preparation of(R)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (109):(R)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (109) was prepared in a similar manner as(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid of Example 106 except using (S)-2-methyl-CBS-oxazaborolidineinstead of (R)-2-methyl-CBS-oxazaborolidine. ¹H NMR (400 MHz, CD₃OD) δ8.59 (d, J=5.3 Hz, 1H), 8.10 (d, J=8.2 Hz, 1H), 7.88 (s, 1H), 7.76 (dd,J=11.1, 8.2 Hz, 1H), 7.63 (d, J=5.3 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H),6.71 (dd, J=12.4, 7.9 Hz, 1H), 5.19 (s, 1H), 4.68 (t, J=6.0 Hz, 2H),3.59 (t, J=6.0 Hz, 2H), 2.70 (s, 3H), 0.85 (s, 8H). ¹⁹F NMR (377 MHz,CD₃OD) δ−77.84 (s), −139.69 (s), −140.48 (s). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₈H₂₆F₂NO₄: 478.5. Found: 478.1.

The other atropisomer,(R)-2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6,7-difluoro-3-methylnaphthalen-2-yl)aceticacid, was prepared in a similar manner. ¹H NMR (400 MHz, CD₃OD) δ 8.70(d, J=5.7 Hz, 1H), 7.96 (s, 1H), 7.86-7.76 (m, 3H), 7.45 (d, J=8.1 Hz,1H), 6.76 (dd, J=12.2, 7.9 Hz, 1H), 5.20 (s, 1H), 4.74 (dt, J=12.4, 6.3Hz, 2H), 3.66 (t, J=5.9 Hz, 2H), 2.76 (s, 3H), 0.92 (s, 9H). ¹⁹F NMR(377 MHz, CD₃OD) δ−77.78 (s, 3F), −138.70—139.02 (m, 1F), −139.80—139.99(m, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₆F₂NO₄: 478.5. Found:478.1.

Example 108(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (110)

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (110):(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (110) was prepared in a similar manner as(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 99 except starting with1-(2,4-difluorophenyl)propan-2-one instead of1-(3-chloro-4-fluorophenyl)propan-2-one.

¹H-NMR: 400 MHz, (CD₃OD) δ: 8.70 (d, J=6.0 Hz, 1H), 8.16 (s, 1H), 7.82(d, J=8.0 Hz, 1H), 7.80 (d, J=6.0 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.17(ddd, J=8.0, 8.0, 2.4 Hz, 1H), 6.43 (d, J=10.0 Hz, 1H), 5.23 (s, 1H),4.71-4.70 (m, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.76 (s, 3H) 0.93 (s, 9H).¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.9 (s, 3F), −112.86 (d, J=7.9 Hz, 1F),−120.76 (dd, J=9.0, 9.0 Hz, IF). LCMS-ESI (m/z): [M+H]⁺ calcd forC₂₈H₂₆F₂NO₄: 478.5. Found: 478.1.

Example 109(2S)-2-tert-Butoxy-2-(5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (111)

Preparation of(2S)-2-tert-butoxy-2-(5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (111):(2S)-2-tert-Butoxy-2-(5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (111) was prepared following the procedure to make(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 99, except 2-(2-chloro-4-fluorophenyl)acetic acid wasused instead of 2-(3-chloro-4-fluorophenyl)acetic acid. ¹H-NMR: 400 MHz,(CDCl₃) δ: 8.59 (s, 1H), 8.30 (s, 1H), 8.11 (d, J=8.21 Hz, 1H), 7.46 (d,J=5.47 Hz, 1H), 7.19 (m, 2H), 6.35 (m. 1H), 5.38 (s, 1H), 4.64 (m, 2H),3.57 (m, 2H), 2.78 (s, 3H), 1.16, 0.98 (s, 9H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₆ClFNO₄: 494.95. found: 494.11.

Example 110(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (112)

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (112):(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (112) was prepared following the procedure to make(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 99, except 2-(4-fluoro-3-methylphenyl)acetic acid wasused instead of 2-(3-chloro-4-fluorophenyl)acetic acid. ¹H-NMR: 400 MHz,(CD₃OD) δ: 8.66 (d, J=5.76 Hz, 1H), 7.90 (s, 1H), 7.80 (d, J=6.65 Hz,3H), 7.42 (d, J=7.82 Hz, 1H), 6.46 (d, J=11.73 Hz, 1H), 5.21 (s, 1H),4.71 (m. 2H), 3.63 (t, J=6.26 Hz, 2H), 2.75 (s, 3H), 2.39 (s, 3H), 0.92(s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₉FNO₄: 474.54. found:474.14.

Example 111(S)-2-tert-Butoxy-2-((R)-5-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (113A) and(S)-2-tert-Butoxy-2-((R)-5-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (113B)

Preparation of(S)-2-tert-butoxy-2-((R)-5-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (113A):(S)-2-tert-butoxy-2-((R)-5-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (113A) was prepared following the procedure to make(S)-2-tert-butoxy-2-((R)-6-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 104, except (S)-ethyl2-tert-butoxy-2-(5-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetatewas used instead of(S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate.¹H-NMR: 400 MHz, (CD₃OD) δ: 8.64 (d, J=5.48 Hz, 1H), 8.22 (s, 1H), 7.92(t, J=7.75 Hz, 1H), 7.76 (d, J=7.82 Hz, 1H), 7.68 (t, J=10.56 Hz, 1H),7.38 (d, J=7.72 Hz, 1H), 6.98 (m, 1H), 5.21 (s, 1H), 4.71 (m. 2H), 3.60(t, J=5.86 Hz, 2H), 2.82 (s, 3H), 0.92 (s, 9H).

¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.8 (s, 3F), −115.5 (br s, 1F). LCMS-ESf⁺(m/z): [M+H]⁺ calcd for C₂₉H₂₆FN₂O₄: 485.52. found: 485.09.

Preparation of(S)-2-tert-butoxy-2-((R)-5-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (113B): Following the procedure to make(S)-2-tert-butoxy-2-((R)-6-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 104, except (S)-ethyl2-tert-butoxy-2-(5-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetatewas used instead of (S)-ethyl2-tert-butoxy-2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate.¹H-NMR: 400 MHz, (CD₃OD) δ: 8.64 (d, J=5.48 Hz, 1H), 8.32 (s, 1H), 7.78(d, J=7.82, 1H), 7.72 (d, J=5.87 Hz, 1H), 7.50 (t, J=8.21 Hz, 1H), 7.40(d, J=8.22 Hz, 1H), 6.68 (m, 1H), 5.21 (s, 1H), 4.75 (m. 2H), 3.60 (t,J=5.87 Hz, 2H), 2.82 (s, 3H), 0.92 (s, 9H).

LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₈FN₂O₅: 503.53. found: 503.12.

Example 112(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid(114)

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate(12 mg, 0.023 mmol, 1 eq.), pyrimidin-5-ylboronic acid (5 mg, 1.5 eq.),Sphos Palladacycle (3 mg, 0.1 eq.), cesium fluoride (12 mg, 3 eq.) andflushed with nitrogen. Dimethoxyethane (0.5 mL, distilled fromNa/benzophenone) was added and mixture sparged with nitrogen for 10minutes and then heated in microwave at 120° C. for 1 hour. The reactionmixture was diluted with ethyl acetate and washed with brine, dried(MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)acetate(4 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₄H₃₃FN₃O₄: 566.63. Found:566.3.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (114): A solution of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methyl-5-(pyrimidin-5-yl)naphthalen-2-yl)acetate(4 mg) and 2 M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) andethanol (0.5 mL) was heated at 50° C. for 3 hours. The reaction mixturewas diluted with ethyl acetate and washed with brine. The aqueous layerwas back-extracted with ethyl acetate and the combined organic layer wasdried (MgSO₄), filtered, concentrated and purified by reverse phase HPLC(Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Product lyophilized to give ayellow powder (1.2 mg). ¹H-NMR: 400 MHz, (CD₃OD): δ 9.23 (d, J=5.09 Hz,1H), 8.82 (s, 1H), 7.96 (s, 1H), 8.60 (m, 1H), 7.80 (m, 1H), 7.52 (d,J=5.08 Hz, 1H), 7.32 (m, 2H), 7.19 (s, 1H), 6.82 (m, 1H), 5.02 (m, 1H),4.76 (m, 2H), 3.50 (t, J=6 Hz, 2H), 2.37 (s, 3H) 0.92 (s, 9H).

¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.7 (s, 6F), −115.9 (m, 1F). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₂H₃₉FN₃O₄: 538.58. Found: 538.03.

Example 113(S)-2-tert-Butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (115)

Preparation of(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (115):(S)-2-tert-Butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (115) was prepared following the procedure to make(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 99, except 2-(3-chloro-2-fluorophenyl)acetic acid wasused instead of 2-(3-chloro-4-fluorophenyl)acetic acid. ¹H-NMR: 400 MHz,(CD₃OD) δ: 8.69 (d, J=5.87 Hz, 1H), 8.18 (s, 1H), 7.80 (m, 2H), 7.42 (d,J=7.72 Hz, 1H), 7.26 (t, J=7.43 Hz, 1H), 6.78 (d, J=9.38 Hz, 1H), 5.22(s, 1H), 4.64 (m, 2H), 3.62 (t, J=5.86 Hz, 2H), 2.80 (s, 3H), 0.98 (s,9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.7 (s, 3F), −127.87 (d, 1F).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₆C1FNO₄: 494.95. found: 494.07.

Example 114(S)-2-tert-Butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (116)

Preparation of 1-(2-chloro-3-methylphenyl)propan-2-one: A Smith processvial was charged with 1-bromo-2-chloro-3-methylbenzene (528 mg, 2.57mmol, 1 eq.), tributylmethoxytin (1.11 mL, 1.5 eq.),4-methylpent-4-en-2-one (0.42 mL, 1.5 eq.), PdCl₂ (23 mg, 5%) andtri(o-tolyl)phosphine (79 mg, 10%), toluene (1 mL) was added and mixturesparged with nitrogen for 10 minutes and then heated in oil bath at 100°C. for 5 hours. The reaction mixture was diluted with ethyl acetate andwashed with brine, dried (MgSO₄), filtered, concentrated and purified byflash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes)to 1-(2-chloro-3-methylphenyl)propan-2-one (375 mg, 80% yield). ¹H-NMR:400 MHz, (CDCl₃) δ: 7.19-7.02 (m, 3H), 3.82 (s, 2H), 2.38 (s, 3H), 2.18(s, 3H).

Preparation of(S)-2-tert-butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (116):(S)-2-tert-butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (116) was prepared following the procedure to make(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid, used 1-bromo-2-chloro-3-methylbenzene instead of2-(3-chloro-4-fluorophenyl)acetic acid. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.59(d, J=5.08 Hz, 1H), 8.26 (s, 1H), 7.68 (m, 2H), 7.34 (d, J=8.21 Hz, 1H),7.08 (d, J=8.60 Hz, 1H), 6.72 (d, J=8.50 Hz, 1H), 5.16 (s, 1H), 4.62 (m,2H), 3.56 (t, J=6.26 Hz, 2H), 2.72 (s, 3H), 2.42 (s, 3H), 0.92 (s, 9H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₉ClNO₄: 490.99. found: 490.33.

Example 115(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5,6-trimethylnaphthalen-2-yl)aceticacid (117)

Preparation (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5,6-trimethylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)acetate(16 mg, 0.031 mmol, 1 eq.), methylboronic acid (4 mg, 2 eq.), SphosPalladacycle (2 mg, 0.1 eq.), cesium fluoride (19 mg, 4 eq.) and flushedwith nitrogen. Dimethoxyethane (0.5 mL, distilled from Na/benzophenone)was added and mixture sparged with nitrogen for 10 minutes and thenheated in microwave at 120° C. for 1 hour. The reaction mixture wasdiluted with ethyl acetate and washed with brine, dried (MgSO₄),filtered, concentrated and purified by flash column chromatography(silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5,6-trimethylnaphthalen-2-yl)acetate(7 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₃₆NO₄: 498.62. Found:498.1.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5,6-trimethylnaphthalen-2-yl)aceticacid (117): A solution of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5,6-trimethylnaphthalen-2-yl)acetate(7 mg) and 2 M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) andethanol (0.5 mL) was heated at 50° C. for 3 hours. The reaction mixturewas diluted with ethyl acetate and washed with brine. The aqueous layerwas back-extracted with ethyl acetate and the combined organic layer wasdried (MgSO₄), filtered, concentrated and purified by reverse phase HPLC(Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Product lyophilized to give ayellow powder (4.7 mg). ¹H-NMR: 400 MHz, (CD₃OD): δ 8.64 (d, J=5.86 Hz,1H), 8.15 (s, 1H), 7.76 (t, J=8.90 Hz, 2H), 7.43 (d, J=8.99 Hz, 1H),7.07 (d, J=8.99 Hz, 1H), 6.65 (d, J=8.60 Hz, 1H), 5.21 (s, 1H), 4.70 (m,2H), 3.64 (t, J=7.77 Hz, 2H), 2.79 (s, 3H), 2.67 (s, 3H), 2.43 (s, 3H),0.92 (s, 9H). LCMS-ESI (m/z): [M+H]⁺ calcd for C₃₀H₃₂NO₄: 470.57. Found:470.39.

Example 116(S)-2-tert-Butoxy-2-((R)-5-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (118)

Preparation of(S)-2-tert-butoxy-2-((R)-5-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (118):(S)-2-tert-butoxy-2-((R)-5-cyano-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (118) was prepared following the procedure to make(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,5,6-trimethylnaphthalen-2-yl)aceticacid of Example 115, except used Zn(CN)₂ was used instead ofmethylboronic acid, and DMF was used instead of DME. Analytical HPLC(Gemini, 2-98% ACN/H₂O+0.05% TFA, 7 minutes run): t_(R) (min)=4.00.

¹H-NMR: 400 MHz, (CD₃OD) δ: 8.59 (d, J=5.48 Hz, 1H), 8.09 (s, 1H), 7.64(d, J=8.21 Hz, 1H), 7.62 (d, J=4.08 Hz, 1H), 7.36 (d, J=8.21 Hz, 1H),7.19 (d, J=8.61 Hz, 1H), 7.12 (d, J=8.98 Hz, 1H), 5.16 (s, 1H), 4.62 (m,2H), 3.56 (t, J=5.86 Hz, 2H), 2.72 (s, 3H), 2.62 (s, 3H), 0.92 (s, 9H).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₂₉N₄O₄: 481.55; found: 481.32.

Example 117(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (119)

Preparation (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate(10 mg, 0.019 mmol, 1 eq.), methylboronic acid (2 mg, 1.5 eq.), SphosPalladacycle (1.3 mg, 0.1 eq.), cesium fluoride (14 mg, 4 eq.) andflushed with nitrogen. Dimethoxyethane (0.5 mL, distilled fromNa/benzophenone) was added and mixture sparged with nitrogen for 10minutes and then heated in microwave at 120° C. for 1 hour. The reactionmixture was diluted with ethyl acetate and washed with brine, dried(MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)acetate(6 mg). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₁H₃₃FNO₄: 502.59. Found:502.1.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (119): A solution of(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)acetate(6 mg) and 2 M sodium hydroxide (0.5 mL) in tetrahydrofuran (0.5 mL) andethanol (0.5 mL) was heated at 50° C. for overnight. The reactionmixture was diluted with ethyl acetate and washed with brine. Theaqueous layer was back-extracted with ethyl acetate and the combinedorganic layer was dried (MgSO₄), filtered, concentrated and purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Productlyophilized to give a yellow powder (4.7 mg). ¹H-NMR: 400 MHz, (CD₃OD):δ 8.67 (d, J=5.47 Hz, 1H), 8.12 (s, 1H), 7.78 (t, J=5.87 Hz, 2H), 7.43(d, J=8.82 Hz, 1H), 7.11 (t, J=8.21 Hz, 1H), 6.63 (d, J=8.60 Hz, 1H),5.22 (s, 1H), 4.70 (m, 2H), 3.64 (t, J=5.86 Hz, 2H), 2.79 (s, 3H), 2.38(d, J=1.47 Hz, 3H), 0.92 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.7 (s,3F), −131.6 (d, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₉FNO₄:474.54. Found: 474.33.

Example 118(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (120)

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (120):(S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (120) was prepared following the procedure to make(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)aceticacid of Example 117, except that ethylboronic acid was used instead ofmethylboronic acid. Analytical HPLC (Gemini, 2-98% ACN/H₂O+0.05% TFA, 7minutes run): t_(R) (min)=4.00.

¹H-NMR: 400 MHz, (CD₃OD): δ 8.67 (d, J=5.47 Hz, 1H), 8.14 (s, 1H), 7.81(t, J=8.21 Hz, 2H), 7.46 (d, J=8.21 Hz, 1H), 7.16 (t, J=8.23 Hz, 1H),6.67 (d, J=9.0 Hz, 1H), 5.22 (s, 1H), 4.71 (m, 2H), 3.66 (t, J=5.86 Hz,2H), 2.79 (m, s, 5H), 1.23 (t, J=7.82 Hz, 3H), 0.93 (s, 9H). ¹⁹F-NMR:377 MHz, (CD₃OD) δ: −77.7 (s, 3F), −133.06 (d, 1F). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₀H₃₁FNO₄: 488.56 (M+H⁺). Found: 488.37.

Example 119(S)-2-tert-Butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (121)

Preparation (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methyl-6-vinylnaphthalen-2-yl)acetate:A Smith process vial was charged with (S)-ethyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate(99 mg, 0.19 mmol, 1 eq.), potassium vinyltrifluoroborate (28 mg, 1.1eq.), Sphos Palladacycle (13 mg, 0.1 eq.), cesium fluoride (114 mg, 4eq.) and flushed with nitrogen. Dimethoxyethane (2 mL, distilled fromNa/benzophenone) was added and mixture sparged with nitrogen for 10minutes and then heated in microwave at 110° C. for 1 hour. The reactionmixture was diluted with ethyl acetate and washed with brine, dried(MgSO₄), filtered, concentrated and purified by flash columnchromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methyl-6-vinylnaphthalen-2-yl)acetate(69 mg, 71% yield). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₃₃FNO₄:514.60. Found: 514.1.

Preparation (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-formyl-3-methylnaphthalen-2-yl)acetate:(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methyl-6-vinylnaphthalen-2-yl)acetate(32 mg, 0.062 mmol, 1 eq.) was dissolved in 2 mL THF. This solution wasadded to the mixture of NaIO₄ (40 mg, 3 eq.) and K₂OsO₄.2H₂O (2.3 mg,0.1 eq.) in 1 mL water at room temperature. The reaction was completeafter stirring at room temperature for 30 minutes. The reaction mixturewas filtered, the filtrate was diluted with ethyl acetate and washedwith brine, dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) togive (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-formyl-3-methylnaphthalen-2-yl)acetateas a light yellow oil (26 mg, 81% yield). LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃₁H₃₁FNO₅: 516.57; Found: 516.1.

Preparation (S)-ethyl2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate:(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-formyl-3-methylnaphthalen-2-yl)acetate(8 mg) was dissolved in 0.5 mL DCM. Deoxofluor (50 μL, excess) was addedto the solution. The reaction was stirred at room temperature for 1hour. The reaction mixture was diluted with ethyl acetate and washedwith brine, dried (MgSO₄), filtered, concentrated and purified by flashcolumn chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) togive (S)-ethyl2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetateas a light yellow oil (6 mg, 76% yield). LCMS-ESI⁺ (m/z): [M+H]⁺ calcdfor C₃₁H₃₁F3NO₅: 538.57. Found: 538.34.

Preparation of(S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (121): A solution of(S)-ethyl2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate(6 mg) in tetrahydrofuran (0.5 mL) and ethanol (0.5 mL) and 2 M sodiumhydroxide (0.5 mL) was heated at 50° C. for 2 hours. The reactionmixture was diluted with ethyl acetate and washed with brine. Theaqueous layer was back-extracted with ethyl acetate and the combinedorganic layer was dried (MgSO₄), filtered, concentrated and purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Productlyophilized to give a yellow powder (4.7 mg). ¹H-NMR: 400 MHz, (CD₃OD):δ 8.69 (d, J=5.48 Hz, 1H), 8.26 (s, 1H), 7.84 (d, J=8.22 Hz, 1H), 7.80(d, J=5.87 Hz, 1H), 7.43 (m, 2H), 7.34, 7.21, 7.07 (t, J=54.74 Hz, 1H),6.90 (d, J=9.38 Hz), 5.25 (s, 1H), 4.73 (m, 2H), 3.64 (t, J=5.86 Hz,2H), 2.83 (s, 3H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.7 (s,3F), −113.97 to −116.29 (m, 2F), −131.6 (s, 1F). LCMS-ESI (m/z): [M+H]⁺calcd for C₂₉H₂₇F₃NO₄: 510.52. Found: 510.36.

Example 120(2S)-2-tert-butoxy-2-(1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)aceticacid (122)

Preparation of ethyl 4-(4-bromophenyl)-3-methylbut-2-enoate: At 0° C., asuspension of 60% w/w NaH/mineral oil (7.13 g, 0.176 mol) in THF (250mL) was treated dropwise with a solution of triethylphosphonoacetate(39.5 g, 0.176 mol) in THF (72 mL) over a 30 min period. The reactionwas stirred for another 30 min, and a solution of1-(4-bromophenyl)propan-2-one (25.0 g, 0.117 mol) in THF (108 mL) wasadded dropwise over 1 h (reaction was kept at 0° C. during addition. Thereaction was allowed to warm to 23° C. as it was stirred overnight. Thenext day, saturated NH₄Cl (250 mL) was added. After 2 h, the reactionwas diluted with H₂O (250 mE) and hexane (100 mL). The organic phase wascollected. The aqueous layer was extracted with EtOAc (2×150 mL).Combined organic phases were dried (MgSO₄), filtered, and concentrated,giving crude 4-(4-bromophenyl)-3-methylbut-2-enoate as a mixture of Eand Z geometric isomers. The residue was carried onward without furtherpurification. (˜30 grams; yield was not determined). The ¹H NMR reportedbelow was from a crude mixture containing both the E and Z isomer.

¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J=8.6 Hz, 1.6H), 7.39 (d, J=8.6 Hz,0.4H), 7.12 (d, J=8.2 Hz, 0.4H), 7.04 (d, J=8.2 Hz, 1.6H), 4.42-4.21 (m,2H), 3.96 (s, 0.4H), 3.38 (s, 1.6H), 2.10 (s, 2.4H), 1.77 (s, 0.6H),1.37-1.23 (m, 3H).

Preparation of 7-bromo-3-methylnaphthalen-1-ol: A flask containing thecrude ethyl 4-(4-bromophenyl)-3-methylbut-2-enoate from above (˜30grams) was treated with concentrated H₂SO₄ (120 mL) and warmed to 50° C.for 2.5 h. The reaction was poured onto ˜500 mL of crushed ice. Once theice had thawed, the brown suspension was extracted with two portions ofEtOAc (500 mL and 100 mL, respectively). The two extracts were combined,washed with saturated NaHCO₃, dried (MgSO₄), filtered, and concentratedto −55 mL. The residue was treated with DCM and wet-loaded onto a silicagel column and purified by flash chromatography (ethyl acetate/hexanes)giving the desired product (16.6 g, 60% yield over 2 steps from1-(4-bromophenyl)propan-2-one. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=1.9Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.50 (dd, J=8.6, 2.0 Hz, 1H), 7.17 (s,1H), 6.67 (s, 1H), 2.42 (s, 3H).

Preparation of 3-methylnaphthalen-1-ol: A slurry of7-bromo-3-methylnaphthalen-1-ol (100 mg, 0.421 mmol), 10% w/w Pd/C (45mg, 42.1 μmol Pd), and absolute EtOH (2.0 mL) was purged under vacuumand backfilled with H₂ from a balloon several times. The suspension wasstirred under a balloon of H₂ at 23° C. overnight. The reaction wasfiltered over Celite, the cake was washed with EtOAc. The filtrate wasconcentrated and dissolved in DCM. The solution was wet-loaded onto a 12g “gold” ISCO silica gel column and purified by flash chromatography(ethyl acetate/hexanes) giving the desired product (yield was notfound). ¹H NMR (400 MHz, CDCl₃) δ 8.10 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8Hz, 1H), 7.47-7.39 (m, 2H), 7.22 (s, 1H), 6.67 (s, 1H), 2.45 (s, 3H).

Preparation of ethyl2-hydroxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate: A flaskcontaining DCM (5.0 mL) was charged with TiCl₄ (1.0 M in DCM, 3.16 mL,3.16 mmol). After cooling to −40° C. (dry ice/CH₃CN bath), a solution of3-methylnaphthalen-1-ol (500 mg, 3.16 mmol) in DCM (5.0 mL) was addeddropwise over a 5 min period. The reaction turned deep violet. After 30min, a solution of ethyl glyoxylate (323 mg, 3.16 mmol, distilledfreshly from P₂O₅under N₂ from the 50% w/w toluene solution of ethylglyoxylate) in DCM (2.0 mL) was added quickly. The reaction was warmedto 0° C. After 1 h, glacial AcOH (1.0 mL) was added. 5 min later, CH₃CN(5.0 mL) was introduced, followed by H₂O (10 mL). The reactiontransitioned from violet to yellow-orange. The reaction was warmed to23° C. and stirred for 30 min. The reaction was diluted with H₂O (15 mL)and extracted with DCM (3×20 mL). The combined extracts were washed withsaturated NaHCO₃ (20 mL) (this decolorized the organic phase from orangeto yellow), dried (Na₂SO₄), filtered, concentrated, treated with DCM (10mL), and concentrated again. The residue was dissolved in DCM and loadedonto a 24 g “gold” ISCO silica gel column and purified by flashchromatography (ethyl acetate/hexanes) giving the desired product (622mg, 76% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 8.20 (d, J=8.2Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.8, 8.0 Hz, 1H), 7.40 (dd,J=8.2, 8.0 Hz, 1H), 7.20 (s, 1H), 5.68 (s, 1H), 4.31-4.08 (m, 2H), 3.94(s, broad, 1H), 2.52 (s, 3H), 1.18 (t, J=7.0 Hz, 3H).

Preparation of ethyl2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate: A solutionof ethyl 2-hydroxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (622 mg,2.39 mmol) in tert-butyl acetate (12 mL) was treated with 70% HClO₄ (20mL) at 23° C.). After 3 h, the reaction was added slowly over 5 min tosaturated NaHCO₃ (25 mL). The resulting system was extracted with DCM(3×15 mL). The combined organic layers were dried (Na₂SO₄), filtered,and concentrated. Hexane (10 mL) was added, and the mixture wasconcentrated again. The residue was dissolved in benzene. The solutionwas wet-loaded onto a 24 g “gold” ISCO silica gel column and purified byflash chromatography (hexane→ethyl acetate) giving the desired product(286 mg, 38% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.26 (d,J=8.2 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.2, 8.0 Hz, 1H),7/39 (dd, J=8.8, 8.0 Hz, 1H), 7.17 (s, 1H), 5.52 (s, 1H), 4.25-4.06 (m,2H), 2.59 (s, 3H), 1.33 (s, 9H), 1.20 (t, J=7.0 Hz, 3H).

Preparation of ethyl2-tert-butoxy-2-(4-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)acetate: Asolution of ethyl2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (1.50 g, 4.74mmol) in CH₃CN (37.5 mL) was cooled to 0° C. Selectfluor (1.70 g, 4.74mmol) was added, and the reaction was allowed to warm to 23° C. After 2h, the reaction was added slowly to a mixture of saturated Na₂HPO₄ (70mL) and H20 (30 mL) at 23° C. More H₂O (40 mL) was added, and the systemwas extracted with DCM (3×40 mL). The combined organic phases weretreated with hexane (20 mL). The phase that separated was removed. Theremaining organic phase was dried (Na₂SO₄), filtered, and concentrated.The filtrate was concentrated and dissolved in benzene. The solution waswet-loaded onto a 24 g “gold” ISCO silica gel column and purified byflash chromatography (ethyl acetate/hexanes) giving the desired product(1.26 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1H), 8.23 (d, J=8.2Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.51 (dd, J=6.9, 6.9 Hz, 1H), 7.45 (dd,J=6.9, 6.9 Hz, 1H), 5.46 (s, 1H), 4.23-4.14 (m, 2H), 2.49 (d, J_(HF)=3.2Hz, 3H), 1.31 (s, 9H), 1.20 (t, J=7.1 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃)δ−137.3 (app. s).

Preparation of ethyl2-tert-butoxy-2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:A flask was charged with Cs₂CO₃ (2.45 g, 7.53 mmol) andN-phenyltriflimide (2.69 g, 7.53 mmol). A solution of ethyl2-tert-butoxy-2-(4-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)acetate(1.26 g, 3.76 mmol) in THF (38 mL) was added at 23° C. After 30 min, thereaction was added slowly to a pre-stirred mixture of 2 M NaHSO₄ (30 mL)and saturated Na₂HPO₄ (100 mL) at 23° C. The system was extracted with amixture of ethyl acetate/hexane (10:1)(3×50 mL). Combined organic layerswere dried (Na₂SO₄), filtered, and concentrated. The residue wasconcentrated once more from hexane. The residue was dissolved inbenzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gelcolumn and purified by flash chromatography (hexane→ethylacetate/hexanes 1:4) giving the desired product (1.75 g, >99%). ¹H NMR(400 MHz, CDCl₃) δ 8.11-8.02 (m, 2H), 7.66-7.60 (m, 2H), 5.72 (s, 1H),4.27-4.10 (m, 2H), 2.44 (d, J_(HF)=3.2 Hz, 3H), 1.21 (s, 9H), 1.18 (t,J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ−123.1 (app. s, 1F), −73.4 (s,3F)

Preparation of ethyl2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)-2-hydroxyacetate:A solution of ethyl2-tert-butoxy-2-(4-fluoro-3-methyl-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(1.75 g, 3.76 mmol) in DCM (30 mL) was treated dropwise with TFA (3.0mL) over 3 min at 23° C. After 16 h, the reaction was diluted with H₂O(60 mL) and the system was extracted with DCM (3×20 mL). Combinedorganic layers were dried (Na₂SO₄), filtered, and concentrated givingthe crude desired product (˜1.54 g obtained), which was used in the nextreaction. ¹H NMR (400 MHz, CDCl₃) δ 8.11-8.06 (m, 1H), 7.67-7.64 (m,1H), 7.61-7.52 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 5.79 (s, 1H), 4.34-4.22(m, 2H), 2.40 (d, J_(HF)=3.2 Hz, 3H), 1.22 (t, J=7.4 Hz, 3H). ¹⁹F NMR(377 MHz, CDCl₃) δ−122.6 (app. s, 1F), −73.3 (s, 3F).

Preparation of ethyl2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)-2-oxoacetate:A solution of ethyl2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate(˜1.54 g, 3.76 mmol) in DCM (60 mL) was treated with Dess-Martinperiodinane (1.91 g, 4.51 mmol) at 23° C. After 4 h, the orange reactionwas slowly added to 10% Na₂S₂O₃ (28 mL) at 23° C. After 5 min ofstirring, the reaction was diluted with H₂O (40 mL) and extracted withDCM (3×20 mL). Combined organic layers were dried (Na₂SO₄), filtered,and concentrated. The residue was dissolved in benzene. The solution waswet-loaded onto a 40 g “gold” ISCO silica gel column and purified byflash chromatography (hexane→ethyl acetate/hexanes 1:4) giving thedesired product (1.08 g, 70% yield over 2 steps from ethyl2-tert-butoxy-2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate).¹H NMR (400 MHz, CDCl₃) δ 8.16-8.08 (m, 2H), 7.76-7.68 (m, 2H), 4.41 (q,J=7.1 Hz, 2H), 2.39 (d, J_(HF)=3.2 Hz, 3H), 1.40 (t, J=7.1 Hz, 3H). ¹⁹FNMR (377 MHz, CDCl₃) δ−122.3 (app. s, 1F), −73.3 (s, 3F).

Preparation of (S)-ethyl2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate:A solution of ethyl2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate(1.08 g, 2.64 mmol) in PhMe (20 mL) was cooled to −40° C. (dry ice/CH₃CNbath). (R) —CBS catalyst (146 mg, 0.528 mmol) was introduced. Distilledcatecholborane (423 μL) was added dropwise over a 5 min period. After 30min, the reaction was warmed to −20° C. and treated with EtOAc (20 mL).Then 15% Na₂CO₃ (10 mL) was added. The reaction was warmed to 23° C. andstirred vigorously. The organic phase was collected after 30 min. It waswashed (vigorous stirring) with 10 mL portions of 15% Na₂CO₃ for 30 mineach until the layer was colorless. (Early washes tended to be darkgreenish-brown). After six such washings, the organic phase was treatedwith saturated NH₄Cl (20 mL) for 30 min. The organic phase was dried(MgSO₄), filtered, and concentrated. The residue was treated withhexanes and concentrated again. The material was dissolved in benzene.The solution was wet-loaded onto a 40 g “gold” ISCO silica gel columnand purified by flash chromatography (hexane→ethyl acetate) giving thedesired product (1.02 g, 94% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.11-8.06(m, 2H), 7.67-7.64 (m, 2H), 5.79 (s, 1H), 4.33-4.22 (m, 2H), 2.40 (d,J_(HF)=3.2 Hz, 3H), 1.22 (t, J=7.4 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃)δ−122.6 (app. s, 1F), −73.1 (s, 3F).

Preparation of (S)-ethyl2-tert-butoxy-2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:A solution of (S)-ethyl2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate(1.02 g, 2.49 mmol) in tert-butyl acetate (20 mL) was treated with 70%HClO₄ (20 μL) at 23° C.). After 5 h, the reaction was added slowly over5 min to saturated NaHCO₃ (40 mL). The resulting system was extractedwith DCM (3×30 mL). The combined organic layers were dried (Na₂SO₄),filtered, and concentrated. The residue was dissolved in benzene. Thesolution was wet-loaded onto a 40 g “gold” ISCO silica gel column andpurified by flash chromatography (hexane→ethyl acetate/hexane 1:4)giving the desired product (942 mg, 81% yield). ¹H NMR (400 MHz, CDCl₃)δ 8.11-8.02 (m, 2H), 7.65-7.60 (m, 2H), 5.72 (s, 1H), 4.25-4.13 (m, 2H),2.45 (d, J_(HF)=3.2 Hz, 3H), 1.21 (s, 9H), 1.18 (t, J=7.0 Hz, 3H). ¹⁹FNMR (377 MHz, CDCl₃) δ−123.1 (ap s, 1F), −73.3 (s, 3F).

Preparation of (2S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetate:The following reaction was run in triplicate: A sealable tube wascharged with 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acidmonohydrochloride (160 mg, 0.636 mmol), S-Phos palladacycle (71.3 mg,0.106 mmol), and CsF (354 mg, 2.33 mmol). The tubes were placed undervacuum, then backfilled with argon. A solution of (S)-ethyl2-tert-butoxy-2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(247 mg, 0.530 mmol) in 1,2-dimethoxyethane (distilled fromNa°/benzophenone, 1.25 mL) was added. The system was stirred for 1 minto dislodge any clumps of solid, then wrapped in foil. The reaction washeated with vigorous stirring to 120° C. for 1.5 h. The three reactionswere cooled to 23° C. and combined by adding to a mixture of brine (30mL) and H₂O (30 mL). The system was extracted with EtOAc (3×30 mL).Combined organic layers were dried (Na₂SO₄), filtered, and concentrated.Hexane was added, and the system was concentrated again. The residue wasdissolved in DCM/PhH 1:1. The solution was wet-loaded onto a 24 g “gold”ISCO silica gel column and purified by flash chromatography(hexane→ethyl acetate) giving the desired product (2S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetate(163 mg, 21% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=8.6 Hz, 1H),7.61-7.18 (m, 6H), 6.92 (d, broad, J=8 Hz, 1H), 5.25 (s, broad, 1H),4.75-4.60 (m, 2H), 4.30-4.00 (m, 2H), 3.55-3.40 (m, 2H), 2.68 (d,J_(HF)=3.2 Hz, 3H), 1.20-1.00 (m, 3H), 0.90 (s, 9H). ¹⁹F NMR (377 MHz,CDCl₃) δ−122 (s, broad) LCMS-ESr (m/z): calcd for C₃₀H₃₀FNO₄: 488.2(M+H⁺). Found: 488.3 (M+H⁺). The other diastereomer was also obtained;(2S)-ethyl2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetate(208 mg, 27% yield):

¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J=8.6 Hz, 1H), 7.50-7.16 (m, 6H),6.88 (d, J=8.2 Hz, 1H), 5.15 (s, 1H), 4.72-4.60 (m, 2H), 4.30-4.00 (m,2H), 3.49-3.38 (m, 2H), 2.61 (d, J_(HF)=3.2 Hz, 3H), 1.27-1.19 (m, 3H),0.83 (s, 9H). ¹⁹F NMR (377 MHz, CDCl₃) δ−124 (app. s, broad). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₃₀H₃₁FNO₄: 488.2. Found: 488.3.

Preparation of(2S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)aceticacid (122): A solution of (2S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetate(163 mg, 0.334 mmol) in THF (6.0 mL) and EtOH (absolute, 2.0 mL) wastreated with LiOH monohydrate (400 mg, 9.48 mmol) in H₂O (2.0 mL). Themixture was stirred vigorously at 100° C. for 2 h. More LiOH monohydrate(600 mg, 14.2 mmol) and H₂O (500 L) were added, and heating wascontinued for another 4 h. The reaction was cooled to 23° C. andfiltered through a 0.45 micron filter pad. The filtrate was purified ona C18 Gemini column (Eluent: H₂O/CH₃CN 95:5→0:100 spiked with 0.1% v/vTFA), giving(2S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)aceticacid as the mono-trifluoroacetic acid salt (124 mg, 64%). ¹H NMR (400MHz, CD₃OD) δ 8.68 (d, J=5.8 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 7.87 (d,J=7.8 Hz, 1H), 7.81 (d, J=5.4 Hz, 1H), 7.60 (dd, J=7.9, 7.4 Hz, 1H),7.48 (d, J=8.2 Hz, 1H), 7.36 (dd, J=7.9, 7.4 Hz, 1H), 6.98 (d, J=8.6 Hz,1H), 5.19 (s, 1H), 4.77-4.70 (m, 2H), 3.67 (dd, J=7.2, 5.9 Hz, 2H), 2.67(d, JH_(F)=3.2 Hz, 3H), 0.97 (s, 9H). ¹⁹F NMR (377 MHz, CD₃OD) δ−77.7(s). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇FNO₄: 460.2; Found: 460.2.The other diastereomer,(2S)-2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)aceticacid, was prepared in a similar manner from (2S)-ethyl2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-4-fluoro-3-methylnaphthalen-2-yl)acetate:¹H NMR (400 MHz, CD₃OD) δ 8.56 (d, J=5.1 Hz, 1H), 8.05 (d, J=8.2 Hz,1H), 7.94 (dd, J=9.0, 5.9 Hz, 1H), 7.88 (s, 1H), 7.54 (d, J=5.6 Hz, 1H),7.38 (d, J=7.8 Hz, 1H), 7.25 (ddd, J=8.7, 8.6, 2.4 Hz, 1H), 6.49 (dd,J=10.3, 2.4 Hz, 1H), 5.22 (s, 1H), 4.67 (dd, J=5.8, 5.8 Hz, 2H), 3.55(dd, J=5.8, 5.8 Hz, 2H), 2.70 (s, 3H), 0.83 (s, 9H). ¹⁹F NMR (377 MHz,CD₃OD) δ−105.6 (s, 1F), −77.6 (s, 3F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇FNO₄: 460.2. Found: 460.5.

Example 121(±)-(2S)-2-tert-Butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (123)

Preparation of ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)acetate:Prepared in a similar manner as2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetateof Example 146 except using 1-(4-fluorophenyl)propan-2-one. ¹H NMR (400MHz, CDCl₃) δ 7.79 (dd, J_(HH)=9.0 Hz, J_(HF)=5.4 Hz, 1H), 7.66 (s, 1H),7.65 (dd, J_(HF)=9.0 Hz, J_(HH)=2.3 Hz, 1H), 7.38 (ddd, J_(HH)=9.0 Hz,J_(HF)=8.0 Hz, J_(HH)=2.3 Hz, 1H), 5.72 (s, 1H), 4.25-4.10 (m, 2H), 2.54(s, 3H), 1.20 (s, 9H), 1.18 (t, J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃)δ−112.0 (ddd, J_(HF)=9.0, 8.0, 5.4 Hz, 1F), −73.4 (s, 3F).

Preparation of (±)-(S)-ethyl2-tert-butoxy-2-((R)1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetate:Prepared in a manner similar to (S)-ethyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetateof Example 99 expect using ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetateas starting material and S-Phos-palladacycle as the catalyst, giving theproduct as a racemate. LCMS-ESI⁺ (m/z): calcd for C₃₀H₃₀FNO₄: 488.2(M+H⁺). Found: 488.2 (M+H⁺). The other diastereomer (+)-(2S)-ethyl2-tert-butoxy-2-((S)1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetatewas also isolated via silica gel chromatography. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₀H₃₁FNO₄: 488.2. Found: 488.2.

Preparation of(±)-(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid (123): Prepared in a similar manner as(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 99, except using (±)-(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetateas the starting material, giving the racemate of the desired product asthe mono-trifluoroacetic acid salt. ¹H NMR (400 MHz, CD₃OD) δ 8.68 (d,J=5.5 Hz, 1H), 8.02-7.97 (m, 2H), 7.81-7.75 (m, 2H), 7.43 (d, J=8.2 Hz,1H), 7.32 (ddd, J=5.4, 5.4, 2.4 Hz, 1H), 6.54 (dd, J=10.0, 2.3 Hz, 1H),5.24 (s, 1H), 4.78-4.67 (m, 2H), 3.67-3.62 (m, 2H), 2.77 (s, 3H), 0.93(s, 9H). ¹⁹F NMR (377 MHz, CD₃OD) δ−105.6 (s, 1F), −77.6 (s, 3F).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇FNO₄: 460.2. Found: 460.4.

The other racemate,(±)-(S)-2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid, was prepared in a similar manner. ¹H NMR (400 MHz, CD₃OD) δ 8.61(d, J=5.8 Hz, 1H), 8.18 (d, J=8.2 Hz, 1H), 7.71 (d, J=5.5 Hz, 1H), 7.58(dd, J=7.0, 6.8 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.34 (dd, J=7.0, 6.8Hz, 1H), 6.96 (d, J=8.6 Hz, 1H), 5.20 (s, 1H), 4.72 (dd, J=6.2, 6.2 Hz,2H), 3.64 (dd, J=6.2, 6.2 Hz, 2H), 2.64 (d, J_(H)F=3.2 Hz, 3H), 0.86 (s,9H). ¹⁹F NMR (377 MHz, CD₃OD) δ−77.8 (s).

LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇FNO₄: 460.2. Found: 460.4.

Example 122(2S)-2-tert-Butoxy-2-((R)-7-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (124)

Preparation of (+)-(2S)-ethyl2-tert-butoxy-2-((R)-(7-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate:Prepared in a manner similar to (S)-ethyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)acetateof Example 99 except using ethyl2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoro-methylsulfonyloxy)naphthalen-2-yl)acetateas the starting material. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₀H₃₁ClNO₄:504.2. Found: 504.2. The other racemate (+)-(2S)-ethyl2-tert-butoxy-2-((S)(7-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetatewas also isolated via silica gel chromatography. LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₃₀H₃₁ClNO₄: 504.2. Found: 504.2.

Preparation of(±)-(S)-2-tert-butoxy-2-((R)-7-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (124):(±)-(S)-2-tert-butoxy-2-((R)-7-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (124) was prepared in a similar manner as(S)-2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid of Example 99, except using (±)-(S)-ethyl2-tert-butoxy-2-((R)-7-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetateas the starting material, giving the racemate of the desired product asthe mono-trifluoroacetic acid salt. ¹H NMR (400 MHz, CD₃OD) δ 8.69 (d,J=5.5 Hz, 1H), 7.99-7.93 (m, 2H), 7.81-7.75 (m, 2H), 7.48-7.43 (m, 2H),6.90 (d, J=2.0 Hz, 1H), 5.22 (s, 1H), 4.77-4.67 (m, 2H), 3.67-3.62 (m,2H), 2.77 (s, 3H), 0.93 (s, 9H). ¹⁹F NMR (377 MHz, CD₃OD) δ−77.6 (s).LCMS-ESI⁺ (m/z): calcd for C₂₈H₂₆ClNO₄: 476.2 (M+H⁺). Found: 476.1(M+H⁺). The other racemate,(±)-(S)-2-tert-butoxy-2-((S)-7-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid, was prepared in a similar manner. ¹H NMR (400 MHz, CD₃OD) δ 8.55(d, J=5.1 Hz, 1H), 8.00 (d, J=6.8 Hz, 1H), 7.88-7.84 (m, 2H), 7.48 (d,broad, J=4 Hz, 1H), 7.40 (dd, J=8.6, 1.8 Hz, 1H), 7.34 (d, J=8.2 Hz,1H), 6.85 (d, J=1.8 Hz, 1H), 5.20 (s, 1H), 4.68-4.62 (m, 2H), 3.54-3.47(m, 2H), 2.69 (s, 3H), 0.80 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₈H₂₇ClNO₄: 476.2. Found: 476.4.

Example 123 Ethyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(125)

Preparation of 3-methyl-4-phenylbutanoic acid: 3-Methyl-4-phenylbutanoicacid was prepared in a similar manner as4-(2-methoxy-phenyl)-3-methyl-butyric acid of Example 32 except using1-phenylpropan-2-one. ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.14 (m, 5H), 2.65(dd, J=13.3, 6.7 Hz, 1H), 2.53 (dd, J=13.3, 7.4 Hz, 1H), 2.38 (dd, 14.9,5.5 Hz, 1H), 2.28 (app. sext. J=6.7 Hz, 1H), 2.17 (dd, 14.5, 7.8 Hz,1H), 0.98 (d, J=6.6 Hz, 3H).

Preparation of 3-methyl-3,4-dihydronaphthalen-1(2H)-one:3-Methyl-3,4-dihydronaphthalen-1(2H)-one was prepared in a similarmanner as 6-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one of Example48, except using 3-methyl-4-phenylbutanoic acid. ¹H NMR (400 MHz, CDCl₃)δ 8.02 (d, J=7.9 Hz, 1H), 7.47 (dd, J=7.4, 7.4 Hz, 1H), 7.31 (dd, J=7.4,7.4 Hz, 1H), 7.24 (d, J=7.4 Hz, 1H), 3.01-2.95 (m, 1H), 2.76-2.66 (m,2H), 2.37-2.27 (m, 2H), 1.15 (d, J=7.2 Hz, 3H).

Preparation of ethyl2-(4-methoxybenzyloxy)-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate:Ethyl2-(4-methoxybenzyloxy)-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate wasprepared in a similar manner as(1-hydroxy-5-methoxy-3-methyl-naphthalen-2-yl)-(4-methoxy-benzyloxy)-aceticacid ethyl ester of Example 32, except using3-methyl-3,4-dihydronaphthalen-1(2H)-one. ¹H NMR (400 MHz, CDCl₃) δ 8.51(s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.48-7.36 (m,2H), 7.27 (d, 8.5 Hz, 2H), 7.18 (s, 1H), 6.89 (d, J=8.4 Hz, 2H), 5.30(s, 1H), 4.67-4.55 (m, 2H), 4.27-4.08 (m, 2H), 3.82 (s, 3H), 2.40 (s,3H), 1.19 (t, J=7.0 Hz, 3H).

Preparation of ethyl2-(4-methoxybenzyloxy)-2-(4-bromo-1-hydroxy-3-methylnaphthalen-2-yl)acetate:A solution of ethyl2-(4-methoxybenzyloxy)-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (102mg, 0.268 mmol) in CHCl₃ (5.0 mL) was treated with solid NaHCO₃ (46 mg,0.281 mmol). Br₂ (45 mg) in CHCl₃ (1.0 mL) was added dropwise over 5 minat 23° C. After 15 min, 10% Na₂S₂O₃ (10 mL) was added. The reaction wasextracted two times with CHCl₃. Combined organic phases were dried(Na₂SO₄), filtered, and concentrated. The residue was dissolved in DCM.The solution was wet-loaded onto a 12 g “gold” ISCO silica gel columnand purified by flash chromatography (ethyl acetate/hexanes) giving thedesired product (83 mg, 67%). ¹H NMR (400 MHz, CDCl₃) 8.69 (s, 1H), 8.29(d, J=8.2 Hz, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.59 (dd, J=7.4, 7.4 Hz, 1H),7.47 (dd, J=7.8, 7.8 Hz, 1H), 7.26 (d, J=8.2 Hz, 2H), 6.91 (d, J=8.6 Hz,2H), 5.47 (s, 1H), 4.67-4.56 (m, 2H), 4.26-4.08 (m, 2H), 3.81 (s, 3H),2.60 (s, 3H), 1.20 (t, J=7.1 Hz, 3H).

Preparation of ethyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(125): Ethyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(125) was prepared in a similar manner as ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateof Example 67 except using ethyl2-(4-methoxybenzyloxy)-2-(4-bromo-1-hydroxy-3-methylnaphthalen-2-yl)acetate.¹H NMR (400 MHz, CDCl₃) 8.39 (d, J=8.6 Hz, 1H), 7.57-7.42 (m, 4H),7.36-7.24 (m, 3H), 5.16 (s, 1H), 4.24-4.09 (m, 2H), 2.75 (s, 3H), 1.23(t, J=7.1 Hz, 3H), 1.00 (s, 9H).

Example 1242-(4-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (126)

Preparation of2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (126): A solution of ethyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(30 mg, 71.4 μmol), LiOH monohydrate (15 mg, 0.357 mmol), H₂O (500 μL),EtOH (absolute, 500 μL), and THF (500 μL) was placed in a sealed tubeand heated to 100° C. Once the reaction was complete, it was cooled to23° C., filtered through a 0.45 micron filter, and directly purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Theproduct-containing fractions were combined and lyophilized, giving thetitle compound (parent form) (11.5 mg, 40%). ¹H NMR (400 MHz, CD₃OD) δ8.38 (d, J=8.6 Hz, 1H), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s,1H), 2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESF (m/z): [M—CO₂—H]⁻ calcd forC₂₂H₂₁BrClO: 415.2. Found: 415.0.

Example 1252-tert-Butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid (127)

Preparation of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetate:A suspension of ethyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(25 mg, 51 μmol), trimethylboroxine (21 μL, 0.153 mmol), PdCl₂(dppf)(3.7 mg, 5.1 μmol), K₂CO₃ (70 mg, 0.510 mmol), PhMe (500 L), EtOH(absolute, 250 μL), and H₂O (250 μL) was stirred in a sealed vessel at100° C. for 3 h. The reaction was cooled to 23° C., diluted with H₂O andextracted with EtOAc (3×). Combined organic phases were dried (Na₂SO₄),filtered, and concentrated, giving crude product. (Yield was not found).¹H NMR (400 MHz, CD₃OD) δ 8.08 (d, J=8.2 Hz, 1H), 7.48-7.44 (m, 3H),7.29-7.26 (m, 4H), 5.15 (s, 1H), 4.20-4.12 (m, 2H), 2.65 (s, 3H), 2.55(s, 3H), 1.21 (t, J=7 Hz, 3H), 1.00 (s, 9H).

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid (127): A solution of the crude ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetatein THF (500 L), EtOH (Absolute, 250 μL), and H₂O (250 μL) was treatedwith LiOH monohydrate (61 mg, 1.45 mmol) and heated to 100° C. in asealed vessel for 4 h. The reaction was cooled to 23° C., filteredthrough a 0.45 micron filter, and directly purified by reverse phaseHPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). The product-containingfractions were combined and lyophilized, giving the title compound(parent form) (8.0 mg, 40% over 2 steps). ¹H NMR (400 MHz, DMSO-d₆) δ12.73 (s, broad, 1H), 8.15 (d, J=8.2 Hz, 1H), 7.72-7.62 (m, 2H),7.57-7.47 (m, 2H), 7.39-7.32 (m, 2H), 7.19 (d, J=8.2 Hz, 1H), 5.07 (s,1H), 2.63 (s, 3H), 2.51 (s, 3H), 0.93 (s, 9H).

LCMS-ESF (m/z): [M−H]⁻ calcd for C₄₈H₄₈Cl₂NaO₆: 813.3. Found: 813.2.

Example 1262-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-vinylnaphthalen-2-yl)aceticacid (128)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-vinylnaphthalen-2-yl)aceticacid (128):2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-vinylnaphthalen-2-yl)aceticacid (128) was prepared in a similar manner as2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid of Example 125, except using potassium vinyltrifluoroborate in theSuzuki coupling reaction, giving the title compound (parent form). ¹HNMR (400 MHz, DMSO-d₆) δ 12.78 (s, broad, 1H), 8.13 (d, J=8.2 Hz, 1H),7.73-7.65 (m, 2H), 7.54-7.48 (m, 2H), 7.41-7.36 (m, 2H), 7.20 (d, J=8.2Hz, 1H), 7.11 (dd, J=18.0, 11.7 Hz, 1H), 5.87 (d, J=11.4 Hz, 1H), 5.41(d, J=18.0 Hz, 1H), 5.09 (s, 1H), 2.50 (s, 3H), 0.94 (s, 9H). LCMS-ESF(m/z): [2M-2H+Na]⁻ calcd for C₅₀H₄₈Cl₂NaO₆: 839.3. Found: 839.2.

Example 1272-tert-Butoxy-2-(1-(4-chlorophenyl)-4-ethyl-3-methylnaphthalen-2-yl)aceticacid (129)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-4-ethyl-3-methylnaphthalen-2-yl)aceticacid (129): A suspension of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-vinylnaphthalen-2-yl)aceticacid (5.0 mg, 12 mol), 5% w/w Rh/Al₂O₃ (10 mg), and EtOH (absolute, 2.0mL) was evacuated and purged several times (vaccuum/H₂ balloon). Thesuspension was rapidly stirred under a balloon of H₂ for 6 h. H₂O (500μL) was added and the reaction was filtered through a 0.45 micronfilter. The filtrate was directly purified by reverse phase HPLC(Gemini, 5 to 100% ACN/H₂O+0.1% TFA). The product-containing fractionswere combined and lyophilized, giving the title compound (parent form)¹H NMR (400 MHz, DMSO-d₆) δ 12.71 (s, broad, 1H), 8.13 (d, J=8.2 Hz,1H), 7.70-7.62 (m, 2H), 7.60-7.47 (m, 2H), 7.34-7.33 (m, 2H), 7.20 (d,J=8.2 Hz, 1H), 5.06 (s, 1H), 3.40-3.20 (m, 2H), 1.25 (t, J=7.4 Hz, 3H),0.93 (s, 9H). LCMS-ESI⁻ (m/z): [2M-2H+Na]⁻ calcd for C₅₀H₅₂Cl₂NaO₆:841.3. Found: 841.3.

Example 128 Ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate(130)

Preparation of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate(130): A solution of ethyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(75 mg, 0.153 mmol), K₂CO₃ (317 mg, 2.29 mmol), PdCl₂(dppf) (11.2 mg,15.3 μmol), and potassium vinyltrifluoroborate (103 mg, 0.766 mmol) inH₂O (500 μL), EtOH (absolute, 500 μL), and PhMe (1.0 mL) was heated to100° C. for 4 h in a sealed vessel. The reaction was cooled to 23° C.,diluted with H₂O (30 mL), and extracted with EtOAc (3×). Combinedorganic phases were dried (Na₂SO₄), filtered, concentrated, andevaporated from MeOH in vacuo (2×). The residue was treated with MeOH(3.0 mL), and DCM (3.0 mL), and cooled to −78° C. The solution wassparged with ozone in O₂ for 5 min. After min past the end of thesparge, the reaction was treated with DMS (100 μL) and warmed to 0° C.10% Na₂S₂O₃ (2.0 mL) was added, and the reaction was stirred at 23° C.for several minutes. The reaction was diluted with H₂O and DCM, thenfiltered over Celite. The filtrate was extracted with DCM (2×). Organicphases were combined, dried (Na₂SO₄), filtered, and concentrated. DCMwas added, and the solution was wet-loaded onto a 12 g “gold” ISCOsilica gel column and purified by flash chromatography (ethylacetate/hexanes 3:97 isocratic) giving the desired product (34 mg, 51%yield). ¹H NMR (400 MHz, DMSO-d₆) 11.01 (s, 1H), 8.73 (d, J=8.2 Hz, 1H),7.56-7.22 (m, 7H), 5.16 (s, 1H), 4.24-4.12 (m, 2H), 2.81 (s, 3H), 1.23(t, J=7.0 Hz, 3H), 1.00 (s, 9H).

Example 1292-tert-Butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (131)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid (131): A solution of ethyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(40 mg, 81.7 μmol), N,N-dimethylpropargylamine (26 μL, 0.245 mmol),PdCl₂(PPh₃)₂ (5.7 mg, 16.3 mol), CuI (3.1 mg, 16.3 μmol) and THF (1.00mL) was heated to 70° C. for 18 h in a sealed vessel. Conversion wasincomplete, so the vessel was charged with more PdCl₂(PPh₃)₂ (5.7 mg,16.3 μmol) and CuI (3.1 mg, 16.3 μmol) and heated to 100° C. for anadditional 26 h. The reaction was cooled to 23° C. THF (1.0 mL), EtOH(absolute, 500 μL), and H₂O (500 L) were added followed by LiOHmonohydrate (100 mg, 2.37 mmol). The reaction was heated to 100° C. for4 h. After cooling to 23° C., the crude reaction was filtered through a0.45 micron filter, and directly purified by reverse phase HPLC (Gemini,5 to 100% ACN/H₂O+0.1% TFA). The product-containing fractions werecombined and lyophilized, giving the title compound (monotrifluoroacetic acid salt) (6.8 mg, 15%). ¹H NMR (400 MHz, DMSO-d₆) δ12.92 (s, broad, 1H), 10.26 (s, broad, 1H), 8.30 (d, J=8.6 Hz, 1H),7.71-7.62 (m, 3H), 7.47-7.43 (m, 2H), 7.34 (d, J=8.2 Hz, 1H), 7.22 (d,J=8.6 Hz, 1H), 5.03 (s, 1H), 4.56 (s, 2H), 2.96 (s, 6H), 2.72 (s, 3H),0.90 (s, 9H). ¹⁹F NMR (377 MHz, DMSO-d₆) δ−74.1 (s) LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₈H₃₁ClNO₃: 464.2. Found: 464.0.

Example 1302-tert-Butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)propyl)-3-methylnaphthalen-2-yl)aceticacid (132)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)propyl)-3-methylnaphthalen-2-yl)aceticacid (132):2-tert-butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)propyl)-3-methylnaphthalen-2-yl)aceticacid (132) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-4-ethyl-3-methylnaphthalen-2-yl)aceticacid of Example 127, except using2-tert-butoxy-2-(1-(4-chlorophenyl)-4-(3-(dimethylamino)prop-1-ynyl)-3-methylnaphthalen-2-yl)aceticacid. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₃₅ClNO₃: 468.2. Found:468.2.

Example 1312-tert-Butoxy-2-(1-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-methylnaphthalen-2-yl)aceticacid (133)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-methylnaphthalen-2-yl)aceticacid (133): A suspension of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate(6.0 mg, 13.9 μmol), EtOH (absolute, 500 μL), NaBH(OAc)₃ (8.8 mg, 41.7μmol), and glacial AcOH (4 μL, 70 μmol) was treated with a solution ofN,N-dimethylamine in MeOH (2 M, 35 L, 69.5 μmol). DCM (50 L) was addedto improve solubility. The reaction was sealed and heated to 70° C.Conversion was limited, so more N,N-dimethylamine in MeOH (2 M, 170 μL,0.337 mmol), glacial AcOH (20 μL, 0.35 mmol), NaBH(OAc)₃ (50 mg, 0.236mmol), and DMF (500 L) were added. Heating was continued. Onceconversion was achieved, LiOH monohydrate (200 mg, 4.7 mmol) and H₂O(1.0 mL) were added. The reaction was sealed and heated to 100° C.overnight. Afterward, the reaction was filtered through a 0.45 micronfilter, and directly purified by reverse phase HPLC (Gemini, 5 to 100%ACN/H₂O+0.1% TFA). The product-containing fractions were combined andlyophilized, giving the title compound (mono trifluoroacetic acid salt)(1.0 mg, 13%). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₆H₃₁ClNO₃: 440.2.Found: 440.0.

Example 1322-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(morpholinomethyl)naphthalen-2-yl)aceticacid (134)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(morpholinomethyl)naphthalen-2-yl)aceticacid (134):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(morpholinomethyl)naphthalen-2-yl)aceticacid (134) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-methylnaphthalen-2-yl)aceticacid of Example 131, except using morpholine in the reductive aminationstep. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₃₃ClNO₄: 482.2. Found:482.0.

Example 1332-tert-Butoxy-2-(1-(4-chlorophenyl)-4-(hydroxymethyl)-3-methylnaphthalen-2-yl)aceticacid (135)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-4-(hydroxymethyl)-3-methylnaphthalen-2-yl)aceticacid (135): A solution of ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-4-formyl-3-methylnaphthalen-2-yl)acetate(6.0 mg, 14 mol), NaBH₄ (1.5 mg, 40 μmol), THF (250 μL), and EtOH(absolute, 500 μL) was stirred at 23° C. for 1 h. H₂O (500 μL) and LiOHmonohydrate (50 mg, 1.18 mmol) were added. The reaction was sealed andheated to 100° C. After 2 h, the reaction cooled to 23° C., filteredthrough a 0.45 micron filter, and directly purified by reverse phaseHPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). The product-containingfractions were combined and lyophilized, giving the title compound(parent form) (2.6 mg, 43%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s, 1H),8.27 (d, J=8.6 Hz, 1H), 7.72-7.65 (m, 2H), 7.58-7.48 (m, 2H), 7.39-7.33(m, 2H), 7.18 (d, J=8.6 Hz, 1H), 5.07 (s, 1H), 5.01 (d, broad, J=2.7 Hz,2H), 2.62 (s, 3H), 0.94 (s, 9H).

LCMS-ESI⁻ (m/z): [M−H]⁻ calcd for C₂₄H₂₄ClO₄: 411.1. Found: 410.9.

Example 1342-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-phenylnaphthalen-2-yl)aceticacid (136)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-phenylnaphthalen-2-yl)aceticacid (136):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-phenylnaphthalen-2-yl)aceticacid (136) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid of Example 125, except using benzeneboronic acid in the Suzukireaction, giving the title compound (parent form). ¹H-NMR: (400 MHz,MeOH— d): δ 7.67-7.55 (m, 5H); 7.50-7.48 (m, 1H); 7.41-7.39 (m, 1H);7.33-7.23 (m, 6H); 5.31 (s, 1H); 2.28 (s, 3H); 1.02 (s, 9H). LCMS-ESF(m/z): [M−H]⁻ calcd for C₂₉H₂₆ClO₃: 457.2. Found: 457.2.

Example 1352-tert-Butoxy-2-(1-(4-chlorophenyl)-4-(6-(dimethylamino)pyridin-3-yl)-3-methylnaphthalen-2-yl)aceticacid (137)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-4-(6-(dimethylamino)pyridin-3-yl)-3-methylnaphthalen-2-yl)aceticacid (137):2-tert-Butoxy-2-(1-(4-chlorophenyl)-4-(6-(dimethylamino)pyridin-3-yl)-3-methylnaphthalen-2-yl)aceticacid (137) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid of Example 125, except using2-(N,N-dimethylamino)-pyridin-5-yl-boronic acid in the Suzuki reaction,giving the title compound. ¹H-NMR: (400 MHz, DMSO-d⁶): δ 8.02-8.00 (m,1H); 7.78 (m, broad, 1H); 7.72-7.69 (m, 1H); 7.67-7.65 (m, 1H);7.52-7.49 (m, 1H); 7.45-7.36 (m, 4H); 7.23 (d, J=8.0 Hz, 2H); 5.11 (s,1H); 2.29 (d, J=1.2 Hz, 3H); 0.93 (d, J=1.2 Hz, 9H). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₀H₃₂ClN₂O₃: 503.2. Found: 503.3.

Example 1362-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyridin-3-yl)naphthalen-2-yl)aceticacid (138)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyridin-3-yl)naphthalen-2-yl)aceticacid (138):2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyridin-3-yl)naphthalen-2-yl)aceticacid (138) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid of Example 125, except using pyridin-3-yl-boronic acid in theSuzuki reaction, giving the title compound (mono trifluoroacetic acidsalt). ¹H-NMR: (400 MHz, DMSO-d⁶): δ 12.8 (s, broad, 1H), 8.80 (d, J=5.1Hz, 1H), 8.62 (d, J=12.9 Hz, 1H), 7.97-7.92 (m, 1H), 7.76-7.69 (m, 3H),7.60-7.54 (m, 1H), 7.47-7.40 (m, 3H), 7.28 (d, J=9.2 Hz, 1H), 7.18 (d,J=9.4 Hz, 1H), 5.15 (s, 1H), 2.25 (s, 3H), 0.96 (s, 9H). ¹⁹F-NMR: (377MHz, DMSO-d⁶): δ−74.7 (s) LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇ClNO₃:460.2; Found: 460.2.

Example 1372-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (139)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (139):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (139) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid of Example 125, except using pyrimidin-5-yl-boronic acid in theSuzuki reaction, giving the title compound (mono trifluoroacetic acidsalt). ¹H-NMR: (400 MHz, DMSO-d⁶): δ 12.87 (s, broad, 1H), 9.39 (s, 1H),8.89-8.86 (m, 2H), 7.76-7.68 (m, 2H), 7.58-7.55 (s, 1H), 7.49-7.44 (m,3H), 7.28 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 5.15 (s, 1H), 2.27(s, 3H), 0.97 (s, 9H). ¹⁹F-NMR: (377 MHz, DMSO-d⁶): δ−73.9 (s) LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₇H₂₆ClN₂O₃: 461.2. Found: 461.2.

Example 1382-(1,4-Bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (140)

Preparation of2-(1,4-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (140):2-(1,4-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (140) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid of Example 125, except using 4-chlorobenzene boronic acid in theSuzuki reaction, giving the title compound (mono trifluoroacetic acidsalt). ¹H-NMR: (400 MHz, DMSO-d⁶): δ 12.82 (s, 1H), 7.75-7.63 (m, 4H),7.55 (dd, J=8.2, 2.4 Hz, 1H), 7.46-7.31 (m, 5H), 7.26-7.21 (m, 2H), 5.14(s, 1H), 2.24 (s, 3H), 0.96 (s, 9H). LCMS-ESF (m/z): [2M-2H+Na]_(r)calcd for C₅₈H₅₀Cl₄NaO₆: 1007.2. Found: 1007.1.

Example 1391-(4-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)prop-2-en-1-ol(141)

Preparation of 1-hydroxy-3-methyl-2-naphthonitrile: Phenyl-2-propanone(24.93 g, 0.178 mol) was combined with ethylcyanoacetate (19.8 mL, 0.180mol), acetic acid (8.0 mL, 0.14 mol), ammonium acetate (2.82 g, 0.0370mol) and 80 mL of benzene in a round bottom flask equipped with aDean-Stark trap and condenser cooled by a chiller. The reaction washeated to 160° C. for 4 h. The mixture was removed from heat and thetrap drained so that the mixture could be concentrated by distilling offexcess (˜50 mL) benzene. The solution contained crude (E)-ethyl2-cyano-3-methyl-4-phenylbut-2-enoate. The concentrated mixture wasremoved from heat and heat adjusted to 240° C. Acetamide (50.9483 g,0.862 mol) was added, and a Claisen head attached to distill any ethanolresulting while the mixture was heated at 240° C. for 60-90 minutes. Themixture was cooled to ˜100° C., and poured into room temperature waterto quench the reaction. A clumpy orange solid was formed, removed byfiltration and triturated with ice cold absolute EtOH. The solid wasfiltered off and the process repeated 4 times to harvest additionalmaterial. The resulting product was a pale yellow fine powder (13.20 g,36% yield). ¹H-NMR: (300 MHz, DMSO-d⁶): δ 11.28 (s, 1H); 8.24 (d, J=8.4Hz, 1H); 7.80 (d, J=8.0 Hz, 1H); 7.62-7.58 (m, 1H); 7.52-7.48 (m, 1H);7.34 (s, 1H); 2.47 (s, 3H).

Preparation of 4-bromo-1-hydroxy-3-methyl-2-naphthonitrile:1-hydroxy-3-methyl-2-naphthonitrile (1.065 g, 5.8 mmol) was dissolvedCHCl₃ (24 mL) and combined with sodium bicarbonate (952 mg, 11.3 mmol)and bromine (330 μL, 6.43 mmol) and allowed to stir at room temperatureovernight. The reaction was quenched by adding 10 mL of 10% sodiumthiosulfate and the mixture stirred until decolorization was maximal.The solids were removed by filtration as crude product (1.47 g, 97%yield.) ¹H-NMR: (300 MHz, DMSO-d⁶): δ 8.334 (d, J=8.0 Hz, 1H); 8.166 (d,J=8.4 Hz, 1H); 7.81-7.77 (m, 1H); 7.65-7.61 (m, 1H); 2.65 (s, 3H).

Preparation of 4-bromo-2-cyanonaphthalen-1-yl perfluorobutanesulfonate:A dichloromethane solution (20 mL) of4-bromo-1-hydroxy-3-methyl-2-naphthonitrile (518 mg, 1.97 mmol) wastreated with triethylamine (800 μL, 5.37 mmol) at −78° C. To this cooledsolution was added nonafluorobutanesulfonic anhydride (1.10 g, 1.97mmol) dropwise as a DCM emulsion. After 15 min reaction was allowed warmto room temp. Reaction was quenched with saturated sodium bicarbonateand allowed to stir at 23° C. overnight. The mixture diluted with DCM,washed with brine and chromatographed on silica gel using EtOAc andhexanes to give desired product (330 mg, 31% yield) as well as recoveredstarting material (245 mg, 47% yield). ¹H-NMR: (400 MHz, DMSO-d₆): δ8.42 (d, J=8.4 Hz, 1H); 8.11 (d, J=8.8 Hz, 1H); 8.05-8.01 (m, 1H);7.99-7.95 (m, 1H); 2.81 (s, 3H).

Preparation of 4-bromo-1-(4-chlorophenyl)-3-methyl-2-naphthonitrile: Toa 50-50 (v/v) EtOH-toluene solution (4 mL) of4-bromo-2-cyanonaphthalen-1-yl perfluorobutanesulfonate (3.99 g, 7.33mmol) in a 2-5 mL microwave vial was added 4-chlorophenylboronic acid(1.65 g, 10.55 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (165 mg, 0.171 mmol) and 6 mL of 2 M K₂CO₃. Thevial was sealed, and heated thermally at 60° C. for minutes. The mixturewas concentrated in vacuo, redissolved in EtOAc and washed withsaturated NH₄Cl and brine then dried with sodium sulfate andconcentrated. The residue was chromatographed on silica gel using EtOAcand hexanes to give a mixture of products. This mixture was thenpurified by hot filtration using neat hexanes (50 mL) to give rise todesired pure product (731 mg, 28% yield). A second crop (600 mg) wasobtained by repeating the hot filtration that was contaminated withstarting material. ¹H-NMR: (400 MHz, MeOH-d⁴): δ 8.361 (d, J=8.4 Hz,1H); 7.89-7.85 (m, 1H); 7.69-7.62 (m, 3H); 7.56-7.49 (m, 3H); 2.81 (s,3H).

Preparation of 4-bromo-1-(4-chlorophenyl)-3-methyl-2-naphthaldehyde:DIBAL-H (11.2 ml, 1.0 M in DCM) was added to a −40° C. DCM solution of4-bromo-1-(4-chlorophenyl)-3-methyl-2-naphthonitrile (2.01 g, 5.63 mmol)slowly. The mixture was allowed to stir and gradually rise to 23° C.over 3-4 hours. The mixture was then cooled back to 0° C. and quenchedwith the addition of EtOAc (15 mL, 18.9 mmol) and stirred with vigor for20-30 minutes. This mixture was poured into 30 mL of saturated NH₄Cl,and stirred 10-15 minutes. After being filtered though a short pad ofCelite followed by extraction with DCM, the extracts were dried withsodium sulfate and concentrated in vacuo. Chromatography on silica gelusing EtOAc in hexanes gave rise to desired aldehyde (1.56 g, 77%yield). ¹H-NMR: (400 MHz, DMSO-d⁶): δ 9.81 (s, 1H); 8.36 (d, J=8.8 Hz,1H); 7.83-7.79 (m, 1H); 7.64-7.62 (m, 1H); 7.60-7.56 (m, 2H); 7.44-7.39(m, 3H); 2.775 (s, 3H).

Preparation1-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)prop-2-en-1-ol(141): To a 0° C. THF (15 mL) solution of4-bromo-1-(4-chlorophenyl)-3-methyl-2-naphthaldehyde (500 mg, 1.39 mmol)was added vinyl magnesium bromide (1.40 mL, 1 M in THF, 1.4 mmol) andthe mixture allowed to stir and warm to 23° C. for 4 hours. Reaction wasquenched by the addition of 10 mL of saturated aqueous NH₄Cl andextracted with ethyl acetate. Extracts were dried with sodium sulfate,concentrated in vacuo and chromatographed on silica gel using EtOAc inhexanes to give desired product (401.8 mg, 75% yield). ¹H-NMR: (400 MHz,CDCl₃): δ 8.40 (d, J=8.8 Hz, 1H); 7.57-7.53 (m, 1H); 7.50-7.44 (m, 2H);7.36-7.32 (m, 1H); 7.25-7.15 (m, 4H); 6.18-6.10 (m, 1H); 5.42-5.40 (m,1H); 5.19-5.03 (m, 2H); 2.79 (s, 3H).

Example 140 Methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-1)-2-tert-butoxyacetate(142)

Preparation of(1-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)allyloxy)(tert-butyl)dimethylsilane:To a stirring 23° C. DCM solution (32 mL) of1-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)prop-2-en-1-ol(1.47 g, 3.79 mmol) and triethylamine (2.3 mL, 16.5 mmol) was addedTBDMS-OTf (2.0 mL, 11.65 mmol) and the reaction was stirred andmonitored by TLC. After 45 minutes, an additional 2 mL of TBDMSOTf wasadded and the mixture allowed to stir overnight. The dark mixture wasthen quenched 10% NaHCO₃ and the color dissipated. The mixture waswashed with brine, dried with sodium sulfate and concentrated in vacuo.Column chromatography using silica gel with EtOAc in hexanes gavedesired silylated product (1.60 g, 84% yield). ¹H-NMR: (400 MHz, CDCl₃):δ 8.39 (d, J=8.4 Hz, 1H); 7.55-745 (m, 3H); 7.34-7.30 m, 1H); 7.26-7.24(m, 1H); 7.24-7.18 (d, J=8.0 Hz, 1H); 7.16-7.14 (m, 1H); 6.09-6.01 (m,1H); 5.32-5.30 (m, 1H); 5.13-5.03 (m, 2H); 2.77 (s, 3H); 0.87 (s, 6H);0.83 (s, 9H).

Preparation of2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetaldehyde:A −78° C. 50-50 (v/v) (MeOH/DCM) solution of(1-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)allyloxy)(tert-butyl)dimethylsilane(1.6 g, 3.19 mmol) was ozonolyzed for 5-10 minutes. The mixture wasquenched with the addition of 1 mL of DMS to and then allowed to warm to23° C. After being diluted with DCM, the mixture was washed with 10%aqueous Na₂S₂O₃ (5×20 mL), dried with sodium sulfate and concentrated invacuo. Silica gel chromatography using EtOAc in Hexanes gave rise todesired aldehyde (1.27 g, 79% yield). ¹H-NMR: 400 MHz, (CDCl₃): δ: 9.94(s, 1H); 8.41-8.36 (d, J=8.0 Hz, 1H); 7.60-7.55 (m, 1H); 7.53-7.45 (m,2H); 7.39-7.32 (m, 2H); 7.29-7.24 (m, 2H); 5.16 (s, 1H); 2.63 (s, 3H);0.86 (m, 15H).

Preparation of2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)aceticacid: A DCM solution (8.0 mL) of2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyl-oxy)acetaldehyde(0.65 g, 1.29 mmol) was combined with 2-methyl-2-butene (1.5 mL, 14.1mmol), sodium dihydrogen phosphate (8.0 mL, 1.0 M) and sodium chlorite(1.37 g, 14.46 mmol) and stirred vigorously overnight. The mixture wasdiluted 200% with DCM, the acidity adjusted to pH<5 with 2 M NaHSO₄ andextracted with DCM (3×20 mL). The extracts were combined dried andconcentrated under vacuo. The crude mixture was observed to contain thedesired carboxylic acid (0.741 g) according to ¹H NMR analysis and wasused without purification. ¹H-NMR: (400 MHz, CD₃OD): δ 8.35 (d, J=8.4Hz, 1H); 7.58-7.51 (m, 3H); 7.46-7.44 (m, 1H); 7.39-7.33 (m, 1H);7.31-7.22 (m, 2H); 5.33 (s, 1H); 2.72 (s, 3H); 0.825 (s, 9H); −0.03 (s,3H); −0.26 (s, 3H).

Preparation of methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetate:Crude2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)aceticacid 0.740 g, 1.4 mmol)was dissolved in 20 mL DCM-MeOH (50-50, v/v) andcombined with TMS-diazomethane solution (7.0 mL, 2.0 M in hexanes) andallowed to stir 6 hrs at 23° C. The reaction was cooled on ice andquenched by the slow addition of TFA (500 μL) which simultaneouslyremoved the yellow color from the reaction mixture. Mixture was dilutedwith DCM and washed with brine, then dried and concentrated in vacuo.Purification by silica gel chromatography with EtOAc in hexanes providedpurified material (537.8 mg, 78% yield) from the2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetaldehyde.¹H-NMR: (400 MHz, MeOH-d⁴): δ 8.39 (d, J=8.0 Hz, 1H); 7.58-7.54 (m, 1H);7.50-7.47 (m, 2H); 7.37-7.33 (m, 2H); 7.27-7.21 (m, 2H); 5.31 (s, 1H);3.69 (s, 3H); 2.67 (s, 3H); 0.83 (s, 9H); −0.04 (s, 3H); −0.27 (s, 3H).

Preparation of methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate:Methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-(tert-butyldimethylsilyloxy)acetate(537.8 mg, 1.01 mmol) was dissolved in 4.0 mL TFA and heated to 60° C.The reaction was monitored by HPLC and turned dark quickly afteraddition of TFA. The reaction was completed after 1 h by HPLC, wasremoved from heat and diluted with toluene (20 mL) and concentrated invacuo. This dilution/concentration was repeated twice more and the colorwas observed to diminished on each cycle. Purification via columnchromatography using silica gel with EtOAc and heptane gave rise todesired product (297.9 mg, 0.71 mmol). ¹H-NMR: (400 MHz, CDCl₃): δ 10.34(s, broad, 1H); 8.40 (d, J=8.0 Hz, 1H); 7.60-7.56 (m, 1H); 7.52-7.46 (m,2H); 7.38-7.35 (m, 1H); 7.32-7.28 (m, 2H); 5.26 (s, 1H); 3.74 (s, 3H);2.62 (s, 3H).

Preparation of methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(142): Methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate(298 mg, 0.71 mmol) was dissolved in t-BuOAc (18.0 mL, 134 mmol) and 7drops of perchloric acid were added. The reaction was monitored by HPLCand TLC for progress. After 4.5 hours, the mixture was added to icysaturated NaHCO₃ and stirred for 10-15 minutes. This mixture wasextracted with EtOAc, extracts dried with sodium sulfate andconcentrated in vacuo. Purification on silica gel using EtOAc in hexanesgave desired product as well as some starting material. ¹H-NMR: (400MHz, CDCl₃): δ 8.39 (d, J=8.8 Hz, 1H); 7.57-7.48 (m, 3H); 7.45-7.42 (m,1H); 7.35-7.31 (m, 1H); 7.28-7.18 (m, 2H); 5.20 (s, 1H); 3.70 (s, 3H);2.72 (s, 3H); 0.99 (s, 9H).

Example 1412-(4-(6-Aminopyridin-3-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (143)

Preparation of2-(4-(6-aminopyridin-3-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (143):2-(4-(6-Aminopyridin-3-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (143) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid of Example 125, except using methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateas the starting material and 2-aminopyridin-5-yl-boronic acid pinacolateester in the Suzuki reaction, giving the title compound (monotrifluoroacetic acid salt). ¹H-NMR: (400 MHz, DMSO-d⁶): δ 8.06-7.86 (m,4H), 7.76-7.68 (m, 2H), 7.56-7.37 (m, 5H), 7.26 (d, J=8.6 Hz, 1H),7.17-7.13 (m, 1H), 5.13 (s, 1H), 2.33 (s, 3H), 0.96 (s, 9H). ¹⁹F-NMR:(377 MHz, DMSO-d⁶): 6-74.2 (s). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₈H₂₈ClN₂O₃: 475.2. Found: 475.2.

Example 1422-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)naphthalen-2-yl)aceticacid (144)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)naphthalen-2-yl)aceticacid (144):2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)naphthalen-2-yl)aceticacid (144) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid of Example 125, except using methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateas the starting material and 2-(1H)pyridone-5-yl-boronic acid pinacolateester in the Suzuki reaction, giving the title compound (parent form).¹H-NMR: (400 MHz, DMSO-d₆): δ 12.8 (s, broad, 1H), 11.8 (app. s, broad,1H), 7.67-7.30 (m, 10H), 7.23 (d, J=8.2 Hz, 1H), 5.11 (s, 1H), 2.36 (s,3H), 0.95 (s, 9H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₈H₂₇ClNO₄: 476.2.Found: 476.2.

Example 1432-(4-(2-Aminopyrimidin-5-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (145)

Preparation of2-(4-(2-aminopyrimidin-5-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (145):2-(4-(2-Aminopyrimidin-5-yl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (145) was prepared in a manner similar to2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)aceticacid of Example 125, except using methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetateas the starting material and 2-aminopyrimidine-5-yl-boronic acidpinacolate ester in the Suzuki reaction, giving the title compound (monotrifluoroacetic acid salt form).

¹H-NMR: (400 MHz, DMSO-d⁶): δ 12.8 (s, broad, 1H), 8.26-8.24 (m, 2H),7.75-7.67 (m, 2H), 7.55 (dd, J=7.8, 2.0 Hz, 1H), 7.53-7.41 (m, 4H), 7.24(d, J=8.2 Hz, 1H), 7.16 (s, broad, 2H), 5.13 (s, 1H), 2.34 (s, 3H), 0.95(s, 9H). ¹⁹F-NMR: (400 MHz, DMSO-d⁶): δ−74.9 (s). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₂₇H₂₇ClN₃O₃: 476.2; Found: 476.2.

Example 1442-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(2-oxo-1,2-dihydropyrimidin-5-yl)naphthalen-2-yl)aceticacid (146)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(2-oxo-1,2-dihydropyrimidin-5-yl)naphthalen-2-yl)aceticacid (146): A suspension methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(10.5 mg, 22.1 μmol), [1H]pyrimidin-2-one-5-yl-boronic acid (25 mg, 0.11mmol), PdCl₂(dppf) (3.2 mg, 4.4 μmol), K₂CO₃ (46 mg, 0.33 mmol), PhMe(500 μL), EtOH (absolute, 250 μL), and H₂O (250 μL) was heated to 100°C. for 30 min, but conversion was poor. The reaction was treated withglacial AcOH (60 μL, 1.05 mmol) and KF (40 mg, 0.688 mmol). MorePdCl₂(dppf) (3.2 mg, 4.4 μmol) and [1H]pyrimidin-2-one-5-yl-boronic acid(7 mg, 30 μmol) were added and the reaction was heated to 100° C. After2 h, the reaction was added to H₂O (15 mL) and glacial AcOH (0.2 mL).The system was extracted with EtOAc (3×10 mL). Combined organic phaseswere dried (Na₂SO₄), filtered, and concentrated. The crude material wastreated with THF (750 μL), EtOH (absolute, 750 μL), H₂O (500 μL), andLiOH monohydrate (50 mg 1.2 mmol). The suspension was heated to 100° C.for 30 min. The reaction was cooled to 23° C., filtered through a 0.45micron filter, and directly purified by reverse phase HPLC (Gemini, 5 to100% ACN/H₂O+0.1% TFA). The product-containing fractions were combinedand lyophilized, giving the title compound (parent form) (3.8 mg, 36%over 2 steps). ¹H-NMR: (400 MHz, DMSO-d⁶): δ 12.8 (s, broad, 1H), 8.29(app. s, broad, 1H), 7.75-7.68 (m, 2H), 7.58-7.44 (m, 4H), 7.43-7.38 (m,2H), 7.25 (d, J=8.2 Hz, 1H), 5.12 (s, 1H), 2.38 (s, 3H), 0.96 (s, 9H).LCMS-ESI (m/z): [M+H]⁺ calcd for C₂₇H₂₆ClN₂O₄: 477.2; Found: 477.2.

Example 1452-tert-Butoxy-2-(1-(4-chlorophenyl)-4-cyano-3-methylnaphthalen-2-yl)aceticacid (147)

Preparation of2-tert-butoxy-2-(1-(4-chlorophenyl)-4-cyano-3-methylnaphthalen-2-yl)aceticacid (147): A suspension of methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate(10.5 mg, 22.1 μmol), CuCN (9.8 mg, 0.11 mmol), and NMP (500 L) washeated to 200° C. in a microwave. The reaction was cooled to 23° C.,treated with EtOH (2.5 mL), filtered through a 0.45 micron filter, anddirectly purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1%TFA). The product-containing fractions were combined and treated withLiOH monohydrate until the pH was distinctly basic. The mixture wasconcentrated with warming to remove most of the water and all of theCH₃CN. The solution was treated with EtOH (absolute, 500 μL) and THF(1.0 mL). The suspension was stirred at 23° C. for 1 h. It was filteredthrough a 0.45 micron filter, and directly purified by reverse phaseHPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). The product-containingfractions were combined and lyophilized, giving the title compound(parent form) (5.2 mg, 55% over 2 steps).

¹H-NMR: (400 MHz, DMSO-d): δ 13.12 (s, 1H), 8.16 (d, J=8.2 Hz, 1H), 7.82(dd, J=7.8, 7.7 Hz, 1H), 7.77-7.70 (m, 2H), 7.60 (dd, J=8.0, 80 Hz, 1H),7.48 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H),5.07 (s, 1 h), 2.83 (s, 3H), 0.95 (s, 9H). LCMS-ESF (m/z): [M−H]⁻ calcdfor C₄₈H₄₃Cl₂N₂O₄: 813.3. Found: 813.3.

Example 146 Ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2oxoacetate(148)

Preparation of ethyl2-(7-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate:Prepared in a manner similar to ethyl2-(6-chloro-7-fluoro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetateof Example 99 except using 1-(4-chlorophenyl)propan-2-one. ¹H-NMR: (400MHz, CDCl₃): δ 8.42 (s, broad, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.59 (d,J=8.6 Hz, 1H), 7.38 (dd, J=8.6, 2.0 Hz, 1H), 7.18 (s, 1H), 5.68 (s, 1H),4.33-4.10 (m, 2H), 2.53 (s, 3H), 1.20 (t, J=7.0 Hz, 3H).

Preparation of ethyl2-tert-butoxy-2-(7-chloro-1-hydroxy-3-methyl-naphthalen-2-yl)acetate:Prepared in a similar manner to ethyl2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate of Example120, except using ethyl2-(7-chloro-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate. ¹H-NMR:(400 MHz, CDCl₃): δ 9.01 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.56 (d, J=8.6Hz, 1H), 7.35 (dd, J=8.6, 2.0 Hz, 1H), 7.13 (s, 1H), 5.49 (s, 1H),4.22-4.08 (m, 2H), 2.56 (s, 3H), 1.31 (s, 9H), 1.19 (t, J=7.0 Hz, 3H).

Preparation of ethyl2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate:Ethyl2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetatewas prepared in a similar manner to ethyl2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)-naphthalen-2-yl)-2-(4-methoxybenzyloxy)acetateof Example 67, except using ethyl2-tert-butoxy-2-(7-chloro-1-hydroxy-3-methylnaphthalen-2-yl)acetate.¹H-NMR: (400 MHz, CDCl₃): δ 8.00 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.6 Hz,1H), 7.65 (s, 1H), 7.49 (dd, J=8.6, 2.0 Hz, 1H), 5.72 (s, 1H), 4.26-4.08(m, 2H), 2.54 (s, 3H), 1.20 (s, 9H), 1.17 (t, J=7.0 Hz, 3H).

¹⁹F-NMR: (377 MHz, CDCl₃): δ 73.2 (s)

Preparation of ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate:Ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate wasprepared in a similar manner to2-(6-chloro-7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetateof Example 99, except using ethyl2-tert-butoxy-2-(7-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. ¹H-NMR: (400 MHz, CDCl₃): δ 8.05 (d, J=2.0 Hz,1H), 7.79 (d, J=8.6 Hz, 1H), 7.74 (s, 1H), 7.58 (dd, J=8.6, 2.0 Hz, 1H),4.41 (q, J=7.0 Hz, 2H), 2.48 (s, 3H), 1.40 (t, J=7.0 Hz, 3H). ¹⁹F-NMR:(377 MHz, CDCl₃): δ−73.2 (s)

Preparation of ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate(148): Ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate(148) was prepared in a manner similar to ethyl2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate ofExample 67, except using ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate.¹H-NMR: (400 MHz, CDCl₃): δ 7.78 (d, J=8.6 Hz, 1H), 7.73 (s, 1H),7.50-7.22 (m, 6H), 4.12 (q, J=7.0 Hz, 2H), 2.49 (s, 3H), 1.13 (t, J=7.0Hz, 3H).

Example 1472-tert-Butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (149)

Preparation of ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate:A solution of ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methyl-naphthalen-2-yl)-2-oxoacetate(26 mg, 67 μmol) in EtOH (absolute, 1.0 mL) and DCM (1.0 mL) was treatedwith NaBH₄ (5.1 mg, 0.134 mmol) at 23° C. After 1 h, saturated NH₄Cl(1.0 mL) was added. The reaction was stirred overnight, then dilutedwith H₂O (10 mL). The mixture was extracted with DCM (3×), and thecombined organics dried (Na₂SO₄), filtered, and concentrated, giving thetitle compound (28 mg, >99% yield). ¹H-NMR: (400 MHz, CDCl₃): δ 7.72 (d,J=8.6 Hz, 1H), 7.65 (s, 1H), 7.51-7.22 (m, 6H), 5.19 (s, 1H), 4.35-4.17(m, 2H), 2.49 (s, 3H), 1.20 (t, J=7.0 Hz, 3H).

Preparation of ethyl2-tert-butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetate:Ethyl2-tert-butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetatewas prepared in a manner similar to (S)-ethyl2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)acetateof Example 51, except using racemic ethyl2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate.Material was carried on crude without further characterization.

Preparation of2-tert-butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (149):2-tert-Butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)aceticacid (149) was prepared in a similar manner to2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid of Example 124, except using ethyl2-tert-butoxy-2-(7-chloro-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)acetate,giving the title compound (parent form) ¹H-NMR: (400 MHz, DMSO-d⁶): δ12.86 (s, broad, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.73-7.67(m, 2H), 7.56-7.49 (m, 2H), 7.40 (d, J=8.2 Hz, 1H), 7.11 (d, J=1.6 Hz,1H), 5.00 (s, 1H), 2.57 (s, 3H), 0.93 (s, 9H). LCMS-ESI⁻ (m/z):[M−H]-calcd for C₂₃H₂₁Cl₂O₃: 415.1. Found: 415.3.

Example 148(R)-2-(4-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (150A) and(S)-2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (150B)

Chiral chromatographic separation of the two enantiomers of methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate:A solution of the racemate (36 mg) in MeOH/EtOH 1:1 v/v (1.8 mL total)was separated preparatively into its two enantiomers on an OJ-H packedchiral column,

(R)-methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate(6.1 mg).

¹H-NMR: (400 MHz, CDCl₃): δ 10.34 (s, broad, 1H); 8.40 (d, J=8.0 Hz,1H); 7.60-7.56 (m, 1H); 7.52-7.46 (m, 2H); 7.38-7.35 (m, 1H); 7.32-7.28(m, 2H); 5.26 (s, 1H); 3.74 (s, 3H); 2.62 (s, 3H). (S)-methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate(4.8 mg)

Preparation of(R)-2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (150A):(R)-2-(4-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (150A) was prepared in a similar manner to2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid of Example 124, except using (R)-methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate,giving the title compound (parent form). ¹H NMR (400 MHz, CD₃OD) δ 8.38(d, J=8.6 Hz, 1H), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s, 1H),2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESF (m/z): [M—CO₂—H]⁻ calcd forC₂₂H₂₁BrClO: 415.2. Found: 415.0.

Preparation of(S)-2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (150B):(S)-2-(4-Bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid (150B) was prepared in a similar manner to2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyaceticacid of Example 124, except using (S)-methyl2-(4-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate,giving the title compound (parent form). ¹H NMR (400 MHz, CD₃OD) δ 8.38(d, J=8.6 Hz, 1H), 7.63-7.47 (m, 4H), 7.38-7.20 (m, 3H), 5.30 (s, 1H),2.69 (s, 3H), 1.00 (s, 9H). LCMS-ESF (m/z): [M—CO₂—H]⁻ calcd forC₂₂H₂₁BrClO: 415.2; Found: 415.0.

Example 149 Compounds 151-180

Compounds 151-180 were prepared by similar methods as described in theabove Examples.

Compound Number Compound Mass Measured mass 151

490 490.33 152

493.96 494.07 153

537.59 538.03 154

484.53 485.1 155

502.54 503.1 156

473.54 474.14 157

394.51 393.0 9(M − H) 158

417.48 418.1 159

417.48 418.1 160

417.48 418.1 161

441.53 442.1 162

459.52 460.16 163

475.97 473.91/475.48 164

509.5 506.1 165

488.6 489.1 166

516.57 517.1 167

501.6 502.1 168

502.54 503.1 169

484.53 485.1 170

499.58 500.2 171

494.96 494.4/496.1 172

477.51 478.1 173

477.51 478.1 174

477.51 478.1 175

467.49 468.1 176

522.64 523.1 177

475.97 474.37 178

459.52 460.5 179

459.52 460.4 180

475.97 476.4

Example 150 Preparation of(S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methynaphthalen-2-yl)aceticacid (181)

Preparation of(S)-ethyl2-tert-butoxy-2-(6-formyl-3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)acetate:A solution of (S)-ethyl2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetate(0.60 g, 1.3 mmol, prepared similarly to (S)-ethyl2-tert-butoxy-2-(7-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)-6-vinylnaphthalen-2-yl)acetatefrom Example 101) in THF (7 mL) at rt was treated with a previouslyprepared mixture of K₂OsO₄.2H₂O (0.023 g, 0.063 mmol) and NaIO₄ (0.81 g,3.8 mmol) in water (5 mL). The resulting suspension becomes thick andopaque. After vigorous stirring for 20 min, the suspension is filteredthrough a pad of Celite, and the filtrate is washed with batches ofEtOAc until white in color. The collected mother liquor is furtherdiluted with water and EtOAc. Following separation, the aqueous layer isextracted with EtOAc until colorless. The combined organics are washedwith brine, dried over anhydrous MgSO₄ and concentrated in vacuo. Theresidue is purified by Yamazen column chromatography (15-35% EtOAc/hex)to afford 0.348 g (60%) of the desired material as a pale yellowamorphous solid. ¹H-NMR: 400 MHz, (CDCl₃) δ: 10.19 (s, 1H); 8.31 (br s,1H); 8.16 (d, J=8.8 Hz, 1H); 8.05 (dd, J=8.8, 1.6 Hz, 1H); 7.85 (s, 1H);5.76 (s, 1H); 4.28-4.10 (m, 2H); 2.61 (s, 3H); 1.22 (s, 9H); 1.18 (t,J=7.2 Hz, 3H).

Preparation of(S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (181): (S)-ethyl2-tert-butoxy-2-(6-formyl-3-methyl-1-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)acetatewas treated to a sequence of synthetic steps with appropriateadjustments for scale similar to the conversion of (S)-ethyl2-tert-butoxy-2-(7-fluoro-6-formyl-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetateto(S)-2-tert-butoxy-2-((R)-6-(difluoromethyl)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-7-fluoro-3-methylnaphthalen-2-yl)aceticacid in Example 101 to produce 0.039 g of the title compound (TFA salt)as an amorphous pale yellow powder. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₂₉H₂₈F₂NO₄: 492.2. found: 492.1. ¹H-NMR: 400 MHz, (CD₃OD) δ: 8.67 (d,J=4.4 Hz, 1H); 8.13 (s, 1H); 8.08 (s, 1H); 7.85-7.99 (m, 2H); 7.46 (d,J=8.8 Hz, 1H); 7.40 (d, J=8.8 Hz, 1H); 7.07 (d, 8.8 Hz, 1H); 6.90 (t,Ji=56 Hz, 1H); 5.26 (s, 1H); 4.77-4.69 (m, 2H); 3.67 (t, J=6 Hz, 2H);2.80 (s, 3H); 0.93 (s, 9H).

Example 151 Preparation of (S)-ethyl2-tert-butoxy-2-(4-carbamoyl-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(182)

Preparation of ethyl2-(4-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate: Asolution of ethyl2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (1.24 g, 3.92mmol) in CHCl₃ (20 mL) was treated with solid NaHCO₃ (843 mg, 9.80mmol). Then a solution of Br₂ (750 mg, 4.70 mmol) in CHCl₃ (5.0 mL) wasadded dropwise over 2 min at 23° C. After 30 min, the reaction wastreated with 10% Na₂S₂O₃ solution (10 mL). After maximum decolorizationwas achieved, the reaction was diluted with H₂O (10 mL) and extractedwith DCM (3×10 mL). Combined organic phases were dried (Na₂SO₄),filtered, and concentrated. The residue was treated with DCM andwet-loaded onto a silica gel column and purified by flash chromatography(ethyl acetate/hexanes) giving the desired product (1.50 g, 97% yield).¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 8.28 (d, J=8.6 Hz, 1H), 8.20 (d,J=8.6 Hz, 1H), 7.56 (dd, J=8.6, 8.6 Hz, 1H), 7.45 (dd, J=8.6, 8.6 Hz,1H), 5.60 (s, 1H), 4.24-4.06 (m, 2H), 2.77 (s, 3H), 1.31 (s, 9H), 1.20(t, J=7.0 Hz, 3H).

Preparation of ethyl 2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate: A flask was charged withN-phenyl-trifluoromethanesulfonimide (2.70 g, 7.57 mmol), Cs₂CO₃ (2.47g, 7.57 mmol), and THF (20 mL). A solution of ethyl2-(4-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (1.50g, 3.78 mmol) in THF (25 mL) was added with stirring at 23° C. After 30min, the reaction was added over 5 min to a premixed solution of 2 MNaHSO₄ (30 mL) and saturated aq. Na₂HPO₄ (100 mL) at 23° C. The systemwas extracted with EtOAc/hexane (10:1, 3×50 mL). Combined organic phaseswere dried (Na₂SO₄), filtered, concentrated, dissolved in hexane, andconcentrated again. The residue was treated with benzene and wet-loadedonto a silica gel column and purified by flash chromatography(hexanes→ethyl acetate/hexanes 1:4) giving the desired product (1.37 g,69% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J=8.8 Hz, 1H), 8.06 (d,J=8.8 Hz, 1H), 7.70 (dd, J=8.8, 8.8 Hz, 1H), 7.64 (dd, J=8.8, 8.8 Hz,1H), 5.77 (s, 1H), 4.28-4.02 (m, 2H), 2.66 (s, 3H), 1.21 (s, 9H), 1.20(t, J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ−73.2 (s).

Preparation ethyl 2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate: A solution of ethyl2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate(1.37 g, 2.60 mmol) in DCM (30 mL) was treated with TFA (3.0 mL) at 23°C. After 2 h, the reaction was diluted with H₂O (30 mL). The organicphase was collected and the aqueous layer was extracted with DCM (2×20mL). Combined organic layers were dried (Na₂SO₄), filtered, andconcentrated giving the desired product as a crude residue (1.22 g),which was immediately used in the next reaction without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J=8.2 Hz, 1H), 8.09 (d,J=8.2 Hz, 1H), 7.71 (dd, J=8.2, 8.2 Hz, 1H), 7.66 (dd, J=8.2, 8.2 Hz,1H), 5.84 (s, 1H), 4.34-4.20 (m, 2H), 2.63 (s, 3H), 1.22 (t, J=7.0 Hz,3H). ¹⁹F NMR (377 MHz, CDCl₃) δ−73.0 (s).

Preparation of ethyl 2-(4-bromo-3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)-2-oxoacetate: A solution of ethyl2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate(crude, 1.22 g, −2.60 mmol) in DCM (60 mL) was treated with Dess-Martinperiodinane (1.32 g, 3.12 mmol) at 23° C. After 30 min, 10% Na₂S₂O₃ (30mL) was added at 23° C. The system was diluted with H₂O (20 mL) andextracted with DCM (3×30 mL). Combined organic layers were dried(Na₂SO₄), filtered, and concentrated. The residue was treated withbenzene, filtered, and wet-loaded onto a silica gel column and purifiedby flash chromatography (ethyl acetate/hexanes) giving the desiredproduct (1.18 g, 98% yield over 2 steps from ethyl2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate).¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=8.6 Hz, 1H), 8.13 (d, J=8.2 Hz,1H), 7.77 (dd, J=8.6, 8.2 Hz, 1H), 7.71 (dd, J=8.6, 8.6 Hz, 1H), 4.42(q, J=7.0 Hz, 2H), 2.57 (s, 3H), 1.39 (t, J=7.0 Hz, 3H). ¹⁹F NMR (377MHz, CDCl₃) δ−73.3 (s).

Preparation of (S)-ethyl2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)-2-hydroxyacetate:A solution of ethyl2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate(1.18 g, 2.52 mmol) in PhMe (20 mL) was cooled to −40° C. (dryice/CH₃CN). (R) —CBS catalyst (140 mg, 0.504 mmol) was introduced,followed by distilled catecholborane (neat, 402 μL, 3.77 mmol) over a 5min period. After 30 min, the reaction was warmed to ˜−20° C. EtOAc (20mL) was added. Then 15% Na₂CO₃ (10 mL) was added. The reaction wasstirred vigorously as it was warmed to 23° C. overnight. The next day,the organic phase was washed (with vigorous stirring) with more 15%Na₂CO₃ (10 mL portions for 30 min each) until the washes were colorless.After the fifth wash, the organic phase was washed once with saturatedNH₄Cl (10 mL) for 10 min, then dried (MgSO₄), filtered, andconcentrated. The residue was dissolved in hexane and re-concentrated.The residue was treated with benzene, filtered, and wet-loaded onto asilica gel column and purified by flash chromatography (ethylacetate/hexanes) giving the desired product (886 mg, 75% yield). ¹H NMR(400 MHz, CDCl₃) δ 8.41 (d, J=8.2 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.71(dd, J=8.6, 8.2 Hz, 1H), 7.66 (dd, J=8.6, 8.6 Hz, 1H), 5.84 (d, J=2.4Hz, 1H), 4.34-4.20 (m, 2H), 3.41 (d, J=2.4 Hz, 1H), 2.63 (s, 3H), 1.22(t, J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ−73.0 (s).

Preparation of (S)-ethyl 2-(4-bromo-3-methyl-1(trifluoromethylsulfonyloxy naphthalen-2-yl)-2-tert-butoxyacetate: Asolution of (S)-ethyl2-(4-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-hydroxyacetate(880 mg, 1.87 mmol) in tert-butyl acetate (20 mL) was treated with 70%HClO₄ (40 μL) at 23° C. After 5 h, the reaction was added slowly over 5min to saturated NaHCO₃ (50 mL) at 23° C. The system was stirred for 10min, then extracted with DCM (3×20 mL). Combined organic layers weredried (Na₂SO₄), filtered, and concentrated. The residue was treated withhexane and concentrated once more. The residue was treated with benzene,filtered, and wet-loaded onto a silica gel column and purified by flashchromatography (ethyl acetate/hexanes) giving the desired product (816mg, 83% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.40 (d, J=7.8 Hz, 1H), 8.06(d, J=7.8 Hz, 1H), 7.70-7.58 (m, 2H), 5.77 (s, 1H), 4.27-4.09 (m, 2H),2.66 (s, 3H), 1.21 (s, 9H), 1.20 (t, J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz,CDCl₃) δ−73.2 (s).

Preparation of (S)-ethyl2-tert-butoxy-2-(4-carbamoyl-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(182): A solution of (S)-ethyl 2-(4-bromo-3-methyl-1(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (200mg, 0.380 mmol) in dry THF (7.6 mL) was cooled to −78° C.tert-butyllithium (1.7 M in pentane, 446 μL, 0.759 mmol) was addeddropwise under N₂ over 3 min. 10 min later, trimethylsilylisocyanate(62.0 μL, 0.456 mmol) was quickly added. The reaction was warmed to 23°C. After 1 h, the system was treated with glacial AcOH (87.0 L, 1.52mmol) followed by EtOH (absolute, 1.9 mL). The reaction was stirred for30 min then diluted with saturated NaHCO₃ (20 mL) and H₂O (10 mL). Thesystem was extracted with DCM (3×15 mL). Combined organic phases weredried (Na₂SO₄), filtered, and concentrated. The residue was treated withbenzene and wet-loaded onto a silica gel column and purified by flashchromatography (ethyl acetate/hexanes) giving the desired product (75mg, 40% yield.) ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.05 (m, 1H), 7.96-7.86(m, 1H), 7.64-7.58 (m, 2H), 6.19 (s, broad, 1H), 6.06 (s, broad, 1H),5.75 (s, 1H), 4.30-4.07 (m, 2H), 2.53 (s, 3H), 1.21 (s, 9H), 1.20 (t,J=7.0 Hz, 3H). ¹⁹F NMR (377 MHz, CDCl₃) δ− 73.2 (s).

Example 153 Preparation of(S)-2-tert-butoxy-2-((R)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (183)

Preparation of(S)-ethyl2-tert-butoxy-2-((R)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate:A vessel was charged with2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, monohydrochloride(49 mg, 0.193 mmol), S-Phos-palladacycle (22 mg, 32.2 mol), and CsF (108mg, 0.708 mmol). The vessel was evacuated under vacuum and backfilledwith argon. A solution of (S)-ethyl2-tert-butoxy-2-(4-carbamoyl-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(182, 79 mg, 0.161 mmol) in 1,2-DME (distilled from Na°/benzophenone,1.4 mL) was added. The vessel was sealed and heated with vigorousstirring to 120° C. for 3 h. The reaction was cooled to 23° C. anddiluted with brine (8 mL) and H₂O (8 mL). The system was extracted withDCM (3×mL). Combined organic layers were dried (Na₂SO₄), filtered, andconcentrated. The residue was dissolved in DCM and concentrated oncemore. The residue was treated with benzene and wet-loaded onto a silicagel column and purified by flash chromatography (ethyl acetate/hexanes)giving (2S)-ethyl2-tert-butoxy-2-((R)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(3.4 mg) in semipure form. LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₁H₃₃N₂O₅:513.2. Found: 513.1. The other diastereomer, (2S)-ethyl2-tert-butoxy-2-((S)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate,was also obtained from the flash column in semipure form (1.3 mg, yieldnot found). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₁H₃₃N₂O₅: 513.2. Found:513.1.

Preparation of(S)-2-tert-butoxy-2-((R)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid (183): A solution of (2S)-ethyl2-tert-butoxy-2-((R)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate (3.4 mg,semipure) in THF (1.0 mL) and EtOH (absolute, 500 μL) was added toLiOH*H₂O (100 mg) predissolved in H₂O (500 μL). The mixture was stirredvigorously at 60° C. for 4 days. The reaction was cooled to 23° C.,diluted with EtOH (absolute, 1.0 mL), and filtered (0.45 micron filter).The filtrate was purified on a C18 Gemini column (eluent: H₂O/CH₃CN95:5-+0:100 spiked with 0.1% v/v TFA), giving(S)-2-tert-butoxy-2-((R)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid as the mono-trifluoroacetic acid salt (1.5 mg, yield not found). ¹HNMR (400 MHz, CD₃OD) δ 8.72-8.69 (m, 1H), 8.06-7.26 (m, 6H), 6.98 (d,J=8.6 Hz, 1H), 5.25 (s, 1H), 3.66-3.32 (m, 2H), 3.30-3.16 (m, 2H), 2.78(s, 3H), 0.94 (s, 9H). ¹⁹F NMR (377 MHz, CDCl₃) δ−77.5 (s). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₉H₂₉N₂O₅: 485.2. Found: 485.1. The otherdiastereomer,(2S)-2-tert-butoxy-2-((S)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)aceticacid, was prepared in a similar manner from (2S)-ethyl2-tert-butoxy-2-((S)-4-carbamoyl-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate:¹H NMR (400 MHz, CD₃OD) δ 8.66-7.19 (m, 7H), 6.96 (d, J=8.6 Hz, 1H),5.25 (s, 1H), 3.67-3.32 (m, 2H), 3.30-3.14 (m, 2H), 2.72 (s, 3H), 0.77(s, 9H). ¹⁹F NMR (377 MHz, CD₃OD) 8-77.6 (s). LCMS-ESI⁺ (m/z): [M+H]⁺calcd for C₂₉H₂₉N₂O₅: 485.2. Found: 485.1.

Example 154 Preparation of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(184)

Preparation of ethyl2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: Ethyl2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate was prepared in a similar fashion to ethyl2-tert-butoxy-2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetatein Example 120 with appropriate adjustments to scale to afford anamorphous white solid that was contaminated with a small amount ofPhNH(Tf). LCMS-ESI⁺ (m/z): [M—C₄H₉+H]⁺ calcd for C₁₆H₁₅F₃O₆S: 392.4.found: 392.6.

Preparation of ethyl2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyl-oxy)naphthalen-2-yl)acetate:A solution of ethyl2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(6.0 grams, ˜13 mmol, semipure) in DCM (60 mL) was treated with TFA (6.0mL) at 23° C. The reaction was diluted with H₂O (60 mL) and the organicphase collected. The aqueous layer was extracted with DCM (2×30 mL). Thecombined organic layers were dried (Na₂SO₄), filtered, and concentrated.The residue (5.5 grams) was used in the next reaction without furtherpurification. ¹H NMR (400 MHz, CDCl₃): δ 8.08-8.06 (m, 1H), 7.81-7.78(m, 1H), 7.69 (s, 1H), 7.62-7.55 (m, 2H), 5.81 (app. s, 1H), 4.35-4.21(m, 2H), 3.26 (app. s, broad, 1H), 2.50 (s, 3H), 1.21 (t, J=7.0 Hz, 3H).

Preparation of ethyl2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate:A solution of ethyl 2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (5.5 g, crude) in DCM (160 mL) was treated withDess-Martin periodinane (7.18 g, 16.9 mmol) at 23° C. After 1 h, thereaction was added slowly over 5 min to 10% Na₂S₂O₃ (100 mL). After 30min, the reaction was extracted with DCM (3×50 mL). The combined organiclayers were dried (Na₂SO₄), filtered, and concentrated. The residue wastreated with benzene, filtered, and wet-loaded onto a silica gel columnand purified by flash chromatography (ethyl acetate/hexanes) giving thedesired product in semipure form (3.9 g). ¹H NMR (400 MHz, CDCl₃): δ8.11-8.08 (m, 1H), 7.86-7.83 (m, 1H), 7.76 (s, 1H), 7.66-7.60 (m, 2H),4.41 (q, J=7.4 Hz, 2H), 2.50 (s, 3H), 1.40 (t, J=7.4 Hz, 3H). ¹⁹F NMR(377 MHz, CDCl₃) δ−73.3 (s).

Preparation of (S)-ethyl2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: Ethyl2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate(1.31 g, 3.3 mmol) was dissolved in toluene (20 mL) and cooled to −40°C. After stirring for 20 minutes, (R)-(+)-2-Methyl-CBS-oxazaborolidine(219 mg, 7.5 mmol) and catechol borane (750 μL, 7.04 mmol) were addedand the mixture stirred at −40° C. After 2 hrs at −40° C. the reactionwas quenched by the addition of 15% Na₂CO₃ (12 mL) and the mixture wasallowed to warm to room temperature. The mixture was washed with 15%Na₂CO₃ (8×12 mL) and saturated NH₄Cl (24 mL), organic layer was driedwith sodium sulfate and concentrated in vacuo. Chromatography usingsilica gel using EtOAc in hexanes produced the desired (S)-ethyl2-hydroxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(976 mg, 1.8 mmol) in 74% yield. ¹H-NMR: 400 MHz, (CDCl₃): δ 8.08-8.06(m, 1H); 7.81-7.79 (m, 1H); 7.69 (s, 1H); 7.60-7.57 (m, 2H); 5.81-5.80(m, 1H); 4.35-4.19 (m, 2H); 3.42 (d, J=2.4 Hz, 1H); 2.50 (s, 3H); 1.21(t, J=7.0 Hz, 3H).

Preparation of (S)-ethyl2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate: To a stirring solution of (560 mg, 1.42 mmol)in t-BuOAc (32.0 mL, 381 mmol) was added 4 drops (catalytic) of 70%HClO₄ and the mixture allowed to stir at room temperature for 2 hours.The mixture was quenched by pouring it into an ice-cold solution ofsaturated NaHCO₃. Extraction with EtOAc (3×20 mL), drying with sodiumsulfate and column chromatography on silica gel using EtOAc in hexanesproduced the desired product (S)-ethyl2-tert-butoxy-2-(3-methyl-1-(trifluoromethyl-sulfonyloxy)naphthalen-2-yl)acetate(455 mg, 71%). ¹H-NMR: 400 MHz, (CDCl₃): δ 8.06-8.03 (m, 1H); 7.81-7.78(m, 1H); 7.67 (s, 1H); 7.59-7.53 (m, 2H); 5.73 (s, 1H); 4.25-4.10 (m,2H); 2.55 (s, 3H); 1.21 (s, 9H), 1.17 (t, J=7.2 Hz, 3H).

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(184): (S)-ethyl2-tert-butoxy-2-(3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate(555 mg, 1.23 mmol) in freshly distilled DME (5.0 mL) was added to a5-10 mL microwave vial charged with a mixture of2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid, HCl salt (368 mg,1.46 mmol); S-Phos palladacycle (155 mg, 0.23 mmol), and CsF (743 mg,4.89 mmol). This heterogeneous mixture was then microwaved at 125° C.for 60 minutes. The mixture was then diluted 400% with EtOAc, extractedwith saturated NH₄Cl, brine, and dried with sodium sulfate.Chromatography via ISCO using a 15 μm particle size silica gel columnseparated the desired atropisomer (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(184) (79.7 mg, 0.17 mmol, 14%) and the undesired atropisomer (S)-ethyl2-tert-butoxy-2-((S)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(109.9 mg, 0.234 mmol). ¹H-NMR: 400 MHz, (CDCl₃): δ 8.66 (d, J=4.4 Hz,1H); 7.77 (d, J=8.0 Hz, 1H); 7.72 (s, 1H); 7.50 (d, J=8.0 Hz, 1H);7.36-7.33 (m, 1H); 7.13-7.01 (m, 4H); 5.09 (s, 1H); 4.58-4.52 (m, 2H);4.03-3.78 (m, 2H); 3.38-3.23 (m, 2H); 2.79 (s, 3H); 0.97 (s, 9H); 0.96(t, J=7.6 Hz, 3H).

Preparation of (S)-ethyl2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate:To a DCM solution (10 mL) of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)acetate(184) (49.0 mg, 0.104 mmol) was added TFA (650 L, 0.0084 mmol) andstirred at rt overnight. The mixture was quenched by pouring into anice-cold solution of saturated NaHCO₃ and extracted with EtOAc to givecrude (S)-ethyl2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate(30.3 mg, 70%). ¹H-NMR: 400 MHz, (CDCl₃): δ 8.67 (d, J=4.0 Hz, 1H);7.79-7.76 (m, 2H); 7.48 (d, J=7.6 Hz, 1H); 7.38 (t, J=7.8 Hz, 1H);7.16-7.10 (m, 3H); 6.97 (d, J=8.4 Hz, 1H); 5.36 (s, 1H); 4.58-4.55 (m,2H); 3.89-3.72 (m, 2H); 3.38-3.31 (m, 2H); 2.69 (s, 3H); 1.05 (t, J=7.0Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₆H₂₄NO₄; 414.17. Found:414.1.

Preparation of (S)-ethyl2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetate:(S)-ethyl2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-hydroxyacetate(57.6 mg, 0.139 mmol) was slurried in 2.0 mL of tert-pentyl acetate and500 L of DCM and treated with one drop of 70% perchloric acid. Themixture was allowed to stir 5 hours. The reaction was quenched bypouring into ice-cold saturated NaHCO₃. This mixture was extracted withEtOAc (3×20 mL), dried with sodium sulfate and concentrated in vacuo.Silica gel chromatography using EtOAc in hexanes produced the desired(S)-ethyl2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetate(58 mg). ¹H-NMR: 400 MHz (CDCl₃): δ 8.66 (s, 1H); 7.77-7.75 (m, 2H);7.49 (d, J=8.0 Hz, 1H); 7.35 (t, J=7.6 Hz, 1H), 7.13-7.07 (m, 3H); 7.02(d, J=8.4 Hz, 1H); 5.08 (s, 1H); 4.45 (t, J=5.6 Hz, 2H); 4.02-3.76 (m,2H); 3.39-3.29 (m, 2H); 2.79 (s, 3H); 1.28-1.24 (m, 2H); 0.97-0.84 (m,9H); 0.70 (t, J=7.0 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd forC₃₁H₃₄NO₄: 484.25. Found: 484.14.

Preparation of(S)-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert-pentyloxy)aceticacid (185): (S)-ethyl2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert-pentyloxy)acetate(58 mg, 0.12 mmol) was dissolved in THF (6.0 mL), MeOH (2 mL) and water(2 mL). LiOH was added (209 mg, 4.98 mmol) and the mixture wasmicrowaved at 100° C. for 45 minutes. The mixture was then diluted 400%with EtOAc, washed with water, brine, dried and concentrated in vacuo.The crude product was dissolved in MeOH and purified via preparatoryHPLC and lyophilized to produce(S)-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yl)-2-(tert-pentyloxy)aceticacid (185) as the TFA salt (11.6 mg). ¹H-NMR: 400 MHz, (CD₃OD): δ 8.67(d, J=5.6 Hz, 1H); 7.97 (s, 1H), 7.94 (d, J=8.0 Hz, 1H); 7.87 (d, J=8.4Hz, 1H); 7.81 (d, J=5.6 Hz, 1H); 7.51-7.47 (m, 2H); 7.28-7.25 (m, 1H);6.93 (d, J=8.8 Hz, 1H); 5.19 (s, 1H); 4.76-4.67 (m, 2H); 3.67 (t, J=6.0Hz, 2H); 2.78 (s, 3H); 1.29-1.12 (m, 2H); 0.93 (d, J=8.4 Hz, 6H); 0.62(t, J=7.0 Hz, 3H). LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₃₀NO₄: 456.55.Found: 456.11.

Example 156 Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-((dimethylamino)methyl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (186A) and(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)aceticacid (186B)

Preparation of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-(dimethylaminomethyl)-5-fluoro-3-methylnaphthalen-2-yl)acetateand (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)acetateand (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)acetate:(S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-formyl-3-methylnaphthalen-2-yl)acetate(18 mg, 0.035 mmol, 1 eq.) and dimethylamine HCl salt (9 mg, 3 eq.) weremixed in 1 mL MeCN at room temperature for 1 hour. The reaction wascooled to 0° C. and NaHB(OAc)₃ (22 mg, 3 eq.) was added to the reaction.The reaction was stirred at 0° C. then warmed up to room temperature for1 hour. The reaction mixture was diluted with ethyl acetate and washedwith brine, dried (MgSO₄), filtered, concentrated and purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Products werelyophilized to give yellow powders of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-((dimethylamino)methyl)-5-fluoro-3-methylnaphthalen-2-yl)acetate(5 mg); LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₃₇FN₂O₄: 545.66. Found:545.21; and (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)acetate(4 mg), LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₁H₃₂FNO₅: 518.59. Found:518.12.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-((dimethylamino)methyl)-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (186A): A solution of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-((dimethylamino)methyl)-5-fluoro-3-methylnaphthalen-2-yl)acetate(5 mg) in tetrahydrofuran (0.5 mL) and ethanol (0.5 mL) and 2 M sodiumhydroxide (0.5 mL) was heated at 50° C. for 2 hours. The reactionmixture was diluted with ethyl acetate and washed with brine. Theaqueous layer was back-extracted with ethyl acetate and the combinedorganic layer was dried (MgSO₄), filtered, concentrated and purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Productlyophilized to give a yellow powder (3.4 mg). ¹H-NMR: 400 MHz, (CD₃OD):δ 8.55 (d, J=5.08 Hz, 1H), 8.10 (s, 1H), 7.58 (d, J=8.21 Hz, 1H), 7.53(d, J=4.69 Hz, 1H), 7.25 (d, J=8.22 Hz, 1H), 7.18 (dd, J=7.82 Hz, 1H),6.78 (d, J=8.60 Hz, 1H), 5.15 (s, 1H), 4.55 (m, 2H), 4.44 (m, 2H), 3.48(t, J=5.87 Hz, 2H), 2.81 (s, 6H), 2.72 (s, 3H), 0.82 (s, 9H). ¹⁹F-NMR:377 MHz, (CD₃OD) δ: −77.7 (s, 3F), −126.37 (s, 1F). LCMS-ESI⁺ (m/z):[M+H]⁺ calcd for C₃₁H₃₄FN₂O₄: 517.60. Found: 517.17.

Preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)aceticacid (186B): A solution of (S)-ethyl2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-6-(hydroxymethyl)-3-methylnaphthalen-2-yl)acetate(4 mg) in tetrahydrofuran (0.5 mL) and ethanol (0.5 mL) and 2 M sodiumhydroxide (0.5 mL) was heated at 50° C. for 2 hours. The reactionmixture was diluted with ethyl acetate and washed with brine. Theaqueous layer was back-extracted with ethyl acetate and the combinedorganic layer was dried (MgSO₄), filtered, concentrated and purified byreverse phase HPLC (Gemini, 5 to 100% ACN/H₂O+0.1% TFA). Productlyophilized to give a yellow powder (2.1 mg). ¹H-NMR: 400 MHz, (CD₃OD):δ 8.57 (d, J=5.08 Hz, 1H), 8.07 (s, 1H), 7.71-7.66 (m, 2H), 7.34 (d,J=8.22 Hz, 1H), 7.25 (dd, J=7.82 Hz, 1H), 6.66 (d, J=8.60 Hz, 1H), 5.14(s, 1H), 4.62 (m, 2H), 3.54 (t, J=5.87 Hz, 2H), 2.70 (s, 3H), 0.83 (s,9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.7 (s, 3F), −132.63 (d, 1F).LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₂₉H₂₉FNO₅: 490.53. Found: 490.1.

Example 157 Preparation of(S)-2-tert-butoxy-2-(6-chloro-1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (187)

Preparation of(S)-2-tert-butoxy-2-(6-chloro-1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)aceticacid: The title compound was prepared following a procedure similar tomake(S)-2-tert-butoxy-2-((R)-5-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3,6-dimethylnaphthalen-2-yl)aceticacid (116) of Example 114 except 1-bromo-3-chloro-2,4-difluoro-benzenewas used instead of 1-bromo-2-chloro-3-methylbenzene. ¹H-NMR: 400 MHz,(CD₃OD): δ 8.72 (d, J=5.48 Hz, 1H), 8.16 (s, 1H), 7.81 (m, 2H), 7.46 (d,J=8.21 Hz, 1H), 6.65 (d, J=10.56 Hz, 1H), 5.22 (s, 1H), 4.72 (m, 2H),3.66 (dd, J=5.87 Hz, 2H), 2.81 (s, 3H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz,(CD₃OD) δ: −77.8 (s, 3F), −118.07 (d, 1F), −123.12 (s, 1F). LCMS-ESI⁺(m/z): [M+H]⁺ calcd for C₂₈H₂₅ClF₂NO₄: 512.94; Found: 512.1.

Example 158 Preparation of(S)-2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (188)

Preparation of(S)-2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (188): Following a procedure similar to the preparation of(S)-2-tert-butoxy-2-((R)-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (119) of Example 117, (S)-ethyl2-tert-butoxy-2-(6-chloro-1-((R)-2,3-dihydro-pyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)acetate(from Example 157) was used instead of (S)-ethyl2-tert-butoxy-2-((R)-6-chloro-1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methylnaphthalen-2-yl)acetate.¹H-NMR: 400 MHz, (CD₃OD): δ 8.69 (d, J=5.47 Hz, 1H), 8.10 (s, 1H), 7.81(m, 2H), 7.44 (d, J=8.21 Hz, 1H), 6.41 (d, J=10.95 Hz, 1H), 5.21 (s,1H), 4.72 (m, 2H), 3.66 (dd, J=5.86 Hz, 2H), 2.78 (s, 3H), 2.32 (s, 3H),0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ: −77.8 (s, 3F), −117.62 (s,1F), −126.33 (s, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺ calc'd for C₂₉H₂₈F₂NO₄:492.53. Found: 492.06.

Example 159 Preparation of(S)-2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (189)

Preparation of(S)-2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5,7-difluoro-3-methylnaphthalen-2-yl)aceticacid (189): Following a procedure similar to the preparation of(S)-2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-6-ethyl-5-fluoro-3-methylnaphthalen-2-yl)aceticacid (120) of Example 118, (S)-ethyl2-tert-butoxy-2-(6-chloro-1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methylnaphthalen-2-yl)acetate(from Example 157) was used instead of (S)-ethyl2-tert-butoxy-2-(6-chloro-1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5-fluoro-3-methyl-naphthalen-2-yl)acetate.¹H-NMR: 400 MHz, (CD₃OD): δ 8.59 (d, J=5.47 Hz, 1H), 8.00 (s, 1H), 7.69(m, 2H), 7.33 (d, J=8.21 Hz, 1H), 6.32 (d, J=11.34 Hz, 1H), 5.11 (s,1H), 4.61 (m, 2H), 3.55 (dd, J=5.48 Hz, 2H), 2.73 (m, 2H), 2.68 (s, 3H),1.18 (dd, J=7.42 Hz, 2H), 0.93 (s, 9H). ¹⁹F-NMR: 377 MHz, (CD₃OD) δ:−77.6 (s, 3F), −119.81 (s, 1F), −128.26 (s, 1F). LCMS-ESI⁺ (m/z): [M+H]⁺calc'd for C₃₀H₃₀F₂NO₄: 506.55. Found: 506.1.

Example 160 Preparation of(S)-2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methyl-6-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (190)

Preparation of(S)-2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3-methyl-6-(pyrimidin-5-yl)naphthalen-2-yl)aceticacid (190): Following a procedure similar to the preparation of(S)-2-tert-butoxy-2-(1-((R)-2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,7-difluoro-3,6-dimethylnaphthalen-2-yl)aceticacid (188) of Example 158, pyrimidin-5-ylboronic acid was utilizedinstead of methylboronic acid to eventually afford the title compound.¹H-NMR: 400 MHz, (CD₃OD): δ 9.22 (s, 1H), 8.99 (s, 1H), 8.74 (d, J=5.87Hz, 1H), 8.24 (s, 1H), 7.84 (d, J=7.82 Hz 1H), 7.78 (d, J=5.48 Hz 1H),7.46 (d, J=8.12 Hz, 1H), 6.69 (d, J=11.34 Hz, 1H), 5.26 (s, 1H), 4.78(m, 2H), 3.66 (dd, J=5.86 Hz, 2H), 2.82 (m, 2H), 0.93 (s, 9H). ¹⁹F-NMR:377 MHz, (CD₃OD) δ: −77.6 (s, 6F), −118.79 (s, 1F), −125.06 (s, 1F).

LCMS-ESI⁺ (m/z): [M+H]⁺ calcd for C₃₂H₂₈F₂N₃O₄: 556.57. Found: 556.10.

Example 161

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula I (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 01N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X = 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of formula I:

wherein: R¹ is R^(1a) or R^(1b); R² is R^(2a) or R^(2b); R³ is R^(3a) or R^(3b); R^(3′) is R^(3a′) or R^(3b′); R⁴ is R^(4a) or R^(4b); R⁵ is R^(5a) or R^(5b); R⁶ is R^(6a) or R^(6b); R⁷ is R^(7a) or R^(7b); R⁸ is R^(8a) or R^(8b); R^(1a) is selected from: a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl; b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl; c) —C(═O)—R¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl and wherein each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle and heteroaryl of R^(1a) is optionally substituted with one or more Z¹⁰ groups; R^(1b) is selected from: a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³, —O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³, —SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴, —(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, —(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl, —(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle, —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl-(C₂-C₆)alkynyl-heterocycle, —(C₃-C₇)carbocycle-Z¹ or -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the —(C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups; c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and —X(C₁-C₆)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle is substituted with one or more Z⁴groups and optionally substituted with one or more Z¹ groups; e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f), —(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f), —(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f); wherein any (C₁-C₆)alkyl, as part of a group, is optionally substituted with one or more Z¹ groups; R^(2a) is selected from: a) H, (C₁-C₆)alkyl and —O(C₁-C₆)alkyl; b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano; c) C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups; d) —OH, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl, —O(C₃-C₇)cycloalkyl, —Oaryl, —Oheterocycle and —Oheteroaryl; and e) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰, and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; R^(2b) is selected from: a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³, —O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³, —SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴, —(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³, —(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl, —(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle, —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle, —(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle, wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups; c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; d) —X(C₁-C₆)alkyl, X(C₁-C₆)haloalkyl, X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and —X(C₁-C₆)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle is substituted with one or more) Z⁴ groups and optionally substituted with one or more Z¹ groups; e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f), —(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f), —(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f), wherein any (C₁-C₆)alkyl, as part of a group, optionally substituted with one or more Z¹ groups; R^(3a) is (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl-aryl, —(C₁-C₆)alkyl-heterocycle, —(C₁-C₆)alkyl-heteroaryl, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —O(C₃-C₇)cycloalkyl, —Oaryl, —O(C₁-C₆)alkyl-(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl-aryl, —O(C₁-C₆)alkyl-heterocycle or —O(C₁-C₆)alkyl-heteroaryl, wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl of R^(3a) is optionally substituted with one or more groups selected from —O(C₁-C₆)alkyl, halo, oxo and —CN, and wherein any (C₃-C₇)cycloalkyl, aryl, heterocycle or heteroaryl of R^(3a) is optionally substituted with one or more groups selected from (C₁-C₆)alkyl, —O(C₁-C₆)alkyl, halo, oxo and —CN; and R^(3a′) is H; R^(3b) is (C₇-C₁₄)alkyl, (C₃-C₇)carbocycle, aryl, heteroaryl, heterocycle, —(C₁-C₆)alkylOH, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹², —(C₁-C₆)alkyl-O—(C₂-C₆)alkenyl-Z¹², —(C₂-C₆)alkyl-O—(C₂-C₆)alkynyl-Z¹², —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹², —(C₁-C₆)alkyl-S—(C₂-C₆)alkenyl-Z¹², —(C₁-C₆)alkyl-S—(C₂-C₆)alkynyl-Z¹², —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-Z¹², —(C₁-C₆)alkyl-S(O)—(C₂-C₆)alkenyl-Z¹², —(C₁-C₆)alkyl-S(O)—(C₂-C₆)alkynyl-Z¹², —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹², —(C₁-C₆)alkyl-SO₂—(C₂-C₆)alkenyl-Z¹², —(C₂-C₆)alkyl-SO₂—(C₂-C₆)alkynyl-Z¹², —(C₁-C₆)alkyl-NR_(a)R_(b), —(C₁-C₆)alkylOC(O)—NR_(c)R_(d), —(C₁-C₆)alkyl-NR_(a)—C(O)—OR_(b), —(C₁-C₆)alkyl-NR_(a)—C(O)—NR_(a)R_(b), —(C₁-C₆)alkyl-SO₂(C₁-C₆)alkyl, —(C₁-C₆)alkyl-SO₂NR_(c)R_(d), —(C₁-C₆)alkyl-NR_(a)SO₂NR_(c)R_(d), —(C₁-C₆)alkyl-NR_(a)SO₂O(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-NR_(a)SO₂Oaryl, —(C₁-C₆)alkyl-NR_(a)—SO₂—(C₁-C₆)alkyl, —(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₁-C₆)alkyl, —(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkenyl, —(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkynyl, —(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, —(C₁-C₆)alkyl-NR_(a)—SO₂-heteroaryl, —(C₁-C₆)alkyl-NR_(a)—SO₂-heterocycle, —O(C₇-C₁₄)alkyl, —O(C₁-C₆)alkyl-NR_(a)R_(b), —O(C₁-C₆)alkylOC(O)—NR_(c)R_(d), —O(C₁-C₆)alkyl-NR_(a)—C(O)—OR_(b), —O(C₁-C₆)alkyl-NR_(a)—C(O)—NR_(a)R_(b), —O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₁-C₆)alkyl, —O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkenyl, —O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₂-C₆)alkynyl, —O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle, —O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle, —O(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, —O(C₁-C₆)alkyl-NR_(a)—SO₂-heteroaryl, —O(C₁-C₆)alkyl-NR_(a)—SO₂-heterocycle, —O(C₁-C₆)alkyl-NR_(a)—SO₂—NR_(a)R_(b), —O(C₁-C₆)alkyl-NR_(a)—SO₂—(C₃-C₇)carbocycle, —O(C₁-C₆)alkyl-NR_(a)—SO₂-halo(C₃-C₇)carbocycle, —O(C₁-C₆)alkyl-NR_(a)—SO₂-aryl, —O(C₁-C₆)alkyl-NR_(a)SO₂NR_(c)R_(d), —O(C₁-C₆)alkyl-NR_(a)SO₂O(C₃-C₇)carbocycle, —O(C₁-C₆)alkyl-NR_(a)SO₂Oaryl, —Oheteroaryl, —Oheterocycle, —Sheteroaryl, —Sheterocycle, —S(O)heteroaryl, —S(O)heterocycle, —SO₂heteroaryl or —SO₂heterocycle, wherein any (C₁-C₆)alkyl, —(C₇-C₁₄)alkyl, aryl, (C₃-C₇)carbocycle, heteroaryl or heterocycle of R^(3b), either alone or as part of a group, is optionally substituted with one or more Z¹ groups, and R^(3b′) is H, (C₁-C₆)alkyl or —O(C₁-C₆)alkyl; or R^(3b) and R^(3b′) together with the carbon to which they are attached form a heterocycle or (C₃-C₇)carbocycle which heterocycle or (C₃-C₇)carbocycle of R^(3b) and R^(3b′) together with the carbon to which they are attached is optionally substituted with one or more Z¹ groups; R^(4a) is selected from aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R^(4a) is optionally substituted with one or more groups each independently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo; R^(4b) is selected from: a) (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₁-C₆)alkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each optionally substituted with one or more Z¹ groups; b) (C₃-C₁₄)carbocycle, wherein (C₃-C₁₄)carbocycle is optionally substituted with one or more Z groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle; c) spiro-heterocycle and bridged-heterocycle, wherein spiro-heterocycle and bridged-heterocycle are optionally substituted with one or more Z¹ groups, or wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle; and d) aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged-heterocycle, wherein aryl, heteroaryl, spiro-heterocycle, fused-heterocycle and bridged-heterocycle are each independently substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups; or R⁴ and R³ together with the atoms to which they are attached form a macroheterocycle or a macrocarbocycle wherein any macroheterocycle or macrocarbocycle of R⁴ and R³ together with the atoms to which they are attached may be optionally substituted with one or more Z¹ groups; and R^(3′) is H, (C₁-C₆)alkyl or —O(C₁-C₆)alkyl; R^(5a) is selected from: a) halo, nitro and cyano; b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹ groups; and c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰, and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; R^(5b) is selected from: a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkylS(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkylSO₂(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, —(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl, —(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle, —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle, —(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups; c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and —X(C₁-C₆)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups; e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f), —(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f), —(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f), wherein any (C₁-C₆)alkyl, as part of a group, is optionally substituted with one or more Z¹ groups; R^(6a) is selected from: a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl; c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹⁵, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle and heteroaryl of R^(6a) is optionally substituted with one or more Z¹⁰ groups; R^(6b) is selected from: a) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, -halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl, —(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle, —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle, —(C₂-C₈)alkynyl-OR_(a), —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a), —(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle, wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups; c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and —X(C₁-C₆)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups; e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f), —(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f), —(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f), wherein any (C₁-C₆)alkyl, as part of a group, is optionally substituted with one or more Z¹ groups; R^(7a) is selected from: a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl; b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl; c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; and wherein any aryl, heterocycle and heteroaryl of R^(7a) is optionally substituted with one or more Z¹⁰ groups; R^(7b) is selected from: a) —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³, —O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³, —SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴, —(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, —(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂zOaryl, —(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl, —(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle, —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle, —(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, —(C₃-C₇)halocarbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups; b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups; c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; d) —X(C₁-C₆)alkyl, X(C₁-C₆)haloalkyl, X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and —X(C₁-C₆)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups; e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f), —(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f), —(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f), wherein any (C₁-C₆)alkyl, as part of a group, is optionally substituted with one or more Z¹ groups; R^(8a) is selected from: a) halo, nitro and cyano; b) R¹¹, —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹ groups; and c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; R^(8b) is selected from: a) —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-Z¹³, —C(O)—(C₁-C₆)alkyl-Z¹³, —O—(C₁-C₆)alkyl-Z¹³, —S—(C₁-C₆)alkyl-Z¹³, —S(O)—(C₁-C₆)alkyl-Z¹³, —SO₂—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-Z¹⁴, —(C₁-C₆)alkyl-C(O)—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-C(O)—O(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-Z¹³, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, -halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl, —(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle, —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle, —(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle or heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups: b) spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle, wherein any spiro-bicyclic carbocycle, fused-bicyclic carbocycle and bridged-bicyclic carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle wherein the (C₃-C₇)carbocycle or heterocycle is optionally substituted with one or more Z¹ groups; c) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; d) —X(C₁-C₆)alkyl, —X(C₁-C₆)haloalkyl, —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle, wherein any —X(C₁-C₆)alkyl and —X(C₁-C₆)haloalkyl is substituted with one or more Z³ groups and optionally substituted with one or more Z¹ groups, and wherein any —X(C₂-C₆)alkenyl, —X(C₂-C₆)alkynyl and —X(C₃-C₇)carbocycle is substituted with one or more Z⁴ groups and optionally substituted with one or more Z¹ groups; e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is independently substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f), —(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f), —(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f), wherein any (C₁-C₆)alkyl, as part of a group, is optionally substituted with one or more Z¹ groups; or any of R^(5a) and R^(6a), R^(6a) and R^(7a), R^(7a) and R^(8a), R¹ and R⁸ or R¹ and R² together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle is optionally substituted with one or more substituents each independently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂; or any of R⁵ and R⁶, R⁶ and R⁷ or R⁷ and R⁸, together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle are each independently substituted with one or more Z⁷ or Z⁸ groups, wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C₇)carbocycle or 4, 5 or 6-membered heterocycle; or R¹ and R⁸ or R¹ and R² together with the atoms to which they are attached form a 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle, wherein the 5 or 6-membered carbocycle or a 4, 5, 6 or 7-membered heterocycle are each independently substituted with one or more Z⁷ or Z⁸ groups; wherein when two Z⁷ groups are on same atom the two Z⁷ groups together with the atom to which they are attached optionally form a (C₃-C₇)carbocycle or 4, 5 or 6-membered heterocycle; X is independently selected from O, —C(O)—, —C(O)O—, —S—, —S(O)—, —SO₂—, —(C₁-C₆)alkylO—, —(C₁-C₆)alkylC(O)—, —(C₁-C₆)alkylC(O)O—, —(C₁-C₆)alkylS—, —(C₁-C₆)alkylS(O)— and —(C₁-C₆)alkylSO₂—; each Z¹ is independently selected from halo, —NO₂, —OH, ═NOR_(a), —SH, —CN, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl, heterocycle, —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl, —O(C₃-C₇)carbocycle, —O(C₃-C₇)halocarbocycle, —Oaryl, —Oheteroaryl, —Oheterocycle, —S(C₁-C₆)alkyl, —S(C₂-C₆)alkenyl, —S(C₂-C₆)alkynyl, —S(C₁-C₆)haloalkyl, —S(C₃-C₇)carbocycle, —S(C₃-C₇)halocarbocycle, —Saryl, —Sheteroaryl, —Sheterocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₂-C₆)alkenyl, —S(O)(C₂-C₆)alkynyl, —S(O)(C₁-C₆)haloalkyl, —S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle, —SO₂(C₁-C₆)alkyl, —S(O)aryl, —S(O)carbocycle, —S(O)heteroaryl, —S(O)heterocycle, —SO₂(C₂-C₆)alkenyl, —SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, —SO₂aryl, —SO₂heteroaryl, —SO₂heterocycle, —SO₂NR_(c)R_(d), —NR_(c)R_(d), —NR_(a)C(O)R_(a), —NR_(a)C(O)OR_(a), —NR_(a)C(O)NR_(c)R_(d)—NR_(a)SO₂R_(b), —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a), —C(O)R_(a), —C(O)OR_(b), —C(O)NR_(e)R_(d), and —OC(O)NR_(c)R_(d), wherein any (C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)halocarbocycle, (C₃-C₇)carbocycle, aryl, heteroaryl and heterocycle of Z¹, either alone or as part of a group, is optionally substituted with one or more halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b), -heteroaryl, -heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl, —NHheterocycle, or —S(O)₂NR_(c)R_(d); each Z² is independently selected from —NO₂, —CN, spiro-heterocycle, bridge-heterocycle, spiro-bicyclic carbocycle, bridged-bicyclic carbocycle, NR_(a)SO₂(C₃-C₇)carbocycle, —NR_(a)SO₂aryl, —NR_(a)SO₂heteroaryl, —NR_(a)SO₂NR_(e)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl; each Z³ is independently selected from —NO₂, —CN, —OH, oxo, ═NOR_(a), thioxo, -aryl, -heterocycle, -heteroaryl, —(C₃-C₇)halocarbocycle, —O(C₁-C₆)alkyl, —O(C₃-C₇)carbocycle, —Ohalo(C₃-C₇)carbocycle, —Oaryl, —Oheterocycle, —Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle, —S(C₃-C₇)halocarbocycle, —Saryl, —Sheterocycle, —Sheteroaryl, —S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle, —S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SO₂aryl, —SO₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(b), —NR_(a)C(O)R_(b), —C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl; each Z⁴ is independently selected from halogen, (C₁-C₆)alkyl, (C₃-C₇)carbocycle, halo(C₁-C₆)alkyl, —NO₂, —CN, —OH, oxo, ═NOR_(a), thioxo, -aryl, -heterocycle, -heteroaryl, (C₃-C₇)halocarbocycle, —O(C₁-C₆)alkyl, —O(C₃-C₇)carbocycle, —O(C₃-C₇)halocarbocycle, Oaryl, —Oheterocycle, —Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle, —S(C₃-C₇)halocarbocycle, —Saryl, —Sheterocycle, —Sheteroaryl, —S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle, —S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SO₂aryl, —SO₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(b), —NR_(a)C(O)R_(a), —C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl; each Z⁵ is independently selected from —NO₂, —CN, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —NR_(a)SO₂(C₁-C₆)alkyl, —NR_(a)SO₂(C₂-C₆)alkenyl, —NR_(a)SO₂(C₂-C₆)alkynyl, —NR_(a)SO₂(C₃-C₇)carbocycle, —NR_(a)SO₂(C₃-C₇)halocarbocycle, —NR_(a)SO₂aryl, —NR_(a)SO₂heteroaryl, —NR_(a)SO₂heteroaryl, —NR_(a)SO₂heterocycle, —NR_(a)C(O)alkyl, —NR_(a)C(O)alkenyl, —NR_(a)C(O)alkynyl, —NR_(a)C(O)(C₃-C₇)carbocycle, —NR_(a)C(O)(C₃-C₇)halocarbocycle, —NR_(a)C(O)aryl, —NR_(a)C(O)heteroaryl, —NR_(a)C(O)heterocycle, NR_(a)C(O)NR_(c)R_(d) and NR_(a)C(O)OR_(b); each Z⁶ is independently selected from —NO₂, —CN, —NR_(a)R_(a), —NR_(a)C(O)R_(b), —NR_(a)C(O)OR_(b), —C(O)NR_(c)R_(d), —(C₃-C₇)halocarbocycle, -aryl, -heteroaryl, -heterocycle, —Oaryl, —Oheteroaryl, —Oheterocycle, —O(C₃-C₇)halocarbocycle, —O(C₁-C₆)alkyl, —O(C₃-C₇)carbocycle, —Ohalo(C₁-C₆)alkyl, —Saryl, —Sheteroaryl, —Sheterocycle, —S(C₃-C₇)halocarbocycle, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle, —S(C₁-C₆)haloalkyl, —S(O)aryl, —S(O)heteroaryl, —S(O)heterocycle, —S(O)(C₃-C₇)halocarbocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)halo(C₁-C₆)alkyl, —SO₂aryl, —SO₂heteroaryl, —SOz₂heterocycle, —SO₂(C₁-C₆)alkyl, —SO₂halo(C₁-C₆)alkyl, —SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, —SO₂NR_(c)R_(d), —NR_(a)SO₂(C₃-C₇)halocarbocycle, —NR_(a)SO₂aryl, —NR_(a)SO₂heteroaryl, —NR_(a)SO₂heteroaryl, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl; each Z⁷ is independently selected from —NO₂, ═NOR_(a), —CN, —(C₁-C₆)alkyl-Z¹², —(C₂-C₆)alkenyl-Z¹², —(C₂-C₆)alkenylOH, —(C₂-C₆)alkynyl-Z¹², —(C₂-C₆)alkynyl-OH, —(C₁-C₆)haloalkyl-Z¹², —(C₁-C₆)haloalkylOH, —(C₃-C₇)carbocycle-Z¹², —(C₃-C₇)carbocycleOH, —(C₃-C₇)halocarbocycle, —(C₁-C₆)alkylNR_(c)R_(d), —(C₁-C₆)alkylNR_(a)C(O)R_(a), —(C₁-C₆)alkylNR_(a)SO₂R_(a), aryl, heteroaryl, heterocycle, —O(C₁-C₆)alkyl-Z¹², —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl, —O(C₃-C₇)carbocycle, —O(C₃-C₇)halocarbocycle, —Oaryl, —O(C₁-C₆)alkylNR_(c)R_(d), —O(C₁-C₆)alkylNR_(a)C(O)R_(a), —O(C₁-C₆)alkylNR_(a)SO₂R_(a), —Oheteroaryl, —Oheterocycle, —S(C₁-C₆)alkyl-Z¹², —S(C₂-C₆)alkenyl, —S(C₂-C₆)alkynyl, —S(C₁-C₆)haloalkyl, —S(C₃-C₇)carbocycle, —S(C₃-C₇)halocarbocycle, —S(C₁-C₆)alkylNR_(c)R_(d), —S(C₁-C₆)alkylNR_(a)C(O)R_(a), —S(C₁-C₆)alkylNR_(a)SO₂R_(a), —Saryl, —Sheteroaryl, —Sheterocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₂-C₆)alkenyl, —S(O)(C₂-C₆)alkynyl, —S(O)(C₁-C₆)haloalkyl, —S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle, —SO₂(C₁-C₆)alkyl, —S(O)(C₁-C₆)alkylNR_(c)R_(d), —S(O)(C₁-C₆)alkylNR_(a)C(O)R_(a), —S(O)(C₁-C₆)alkylNR_(a)SO₂R_(a), —S(O)aryl, —S(O)heteroaryl, —S(O)heterocycle, —SO₂(C₁-C₆)alkyl, —SO₂(C₂-C₆)alkenyl, —SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, —SO₂aryl, —SO₂heteroaryl, —SO₂heterocycle, —SO₂(C₁-C₆)alkylNR_(c)R_(d), —SO₂(C₁-C₆)alkylNR_(a)C(O)R_(a), —SO₂(C₁-C₆)alkylNR_(a)SO₂R_(a), —SO₂NR_(c)R_(d), —NR_(a)C(O)OR_(b), —NR_(a)C(O)NR_(c)R_(d)—NR_(a)SO₂R_(b), —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a), —C(O)NR_(c)R_(d), and —OC(O)NR_(c)R_(d), wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl and heterocycle of Z⁷, either alone or as part of a group, is optionally substituted with one or more halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b), -heteroaryl, -heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl, —NHheterocycle, or —S(O)₂NR_(c)R_(d); each Z⁸ is independently selected from —NO₂ and —CN; each Z⁹ is independently selected from —(C₁-C₆)alkyl and —O(C₁-C₆)alkyl; each Z¹⁰ is independently selected from: i) halo, oxo, thioxo, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyl-(C₁-C₆)alkyl-, —OH, —O(C₁-C₆)alkyl, —O(C₁-C₆)haloalkyl, —SH, —S(C₁-C₆)alkyl, —SO(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂; ii) (C₁-C₆)alkyl optionally substituted with —OH, —O—(C₁-C₆)haloalkyl or —O—(C₁-C₆)alkyl; and iii) aryl, heterocycle and heteroaryl, which aryl, heterocycle and heteroaryl is optionally substituted with halo, (C₁-C₆)alkyl or COOH; each Z¹¹ is independently selected from Z¹⁰, —C(═O)—NH₂, —C(═O)—NH(C₁-C₄)alkyl, —C(═O)—N((C₁-C₄)alkyl)₂, —C(═O)-aryl, —C(═O)-heterocycle and —C(═O)-heteroaryl; each Z¹² is independently selected from —NO₂, ═NOR_(a), thioxo, aryl, heterocycle, heteroaryl, (C₃-C₇)halocarbocycle, (C₃-C₇)carbocycle, —O(C₃-C₇)carbocycle, —Ohalo(C₃-C₇)carbocycle, —Oaryl, —Oheterocycle, —Oheteroaryl, —S(C₁-C₆)alkyl, —S(C₃-C₇)carbocycle, —Shalo(C₃-C₇)carbocycle, —Saryl, —Sheterocycle, —Sheteroaryl, —S(O)(C₁-C₆)alkyl, —S(O)(C₃-C₇)carbocycle, —S(O)halo(C₃-C₇)carbocycle, —S(O)aryl, —S(O)heterocycle, —S(O)heteroaryl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, SO₂aryl, SO₂heterocycle, —SO₂heteroaryl, —NR_(a)R_(a), —NR_(a)C(O)R_(b), —C(O)NR_(c)R_(d), —SO₂NR_(c)R_(d), —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle and —NR_(a)SO₂Oaryl; each Z¹³ is independently selected from —NO₂, —OH, ═NOR_(a), —SH, —CN, (C₃-C₇)halocarbocycle, —O(C₁-C₆)alkyl, —O(C₂-C₆)alkenyl, —O(C₂-C₆)alkynyl, —O(C₁-C₆)haloalkyl, —O(C₃-C₇)carbocycle, —O(C₃-C₇)halocarbocycle, —Oaryl, —Oheteroaryl, —Oheterocycle, —S(C₁-C₆)alkyl, —S(C₂-C₆)alkenyl, —S(C₂-C₆)alkynyl, —S(C₁-C₆)haloalkyl, —S(C₃-C₇)carbocycle, —S(C₃-C₇)halocarbocycle, —Saryl, —Sheteroaryl, —Sheterocycle, —S(O)(C₁-C₆)alkyl, —S(O)(C₂-C₆)alkenyl, —S(O)(C₂-C₆)alkynyl, —S(O)(C₁-C₆)haloalkyl, —S(O)(C₃-C₇)carbocycle, —S(O)(C₃-C₇)halocarbocycle, —S(O)aryl, —S(O)heteroaryl, —S(O)heterocycle, —SO₂(C₁-C₆)alkyl, —SO₂(C₂-C₆)alkenyl, —SO₂(C₂-C₆)alkynyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(C₃-C₇)carbocycle, —SO₂(C₃-C₇)halocarbocycle, —SO₂aryl, —SO₂heteroaryl, —SO₂heterocycle, —SO₂NR_(c)R_(d), —NR_(c)R_(d), —NR_(a)C(O)R_(a), —NR_(a)C(O)OR_(b), —NR_(a)C(O)NR_(e)R_(d)—NR_(a)SO₂R_(b), —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —OS(O)₂R_(a), —C(O)R_(a), —C(O)OR_(b), —C(O)NR_(c)R_(d), and —OC(O)NR_(e)R_(d), wherein any (C₁-C₆)alkyl, —(C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —(C₃-C₇)halocarbocycle, (C₃-C₇)carbocycle, (C₃-C₇)halocarbocycle, aryl, heteroaryl or heterocycle of Z¹³, either alone or as part of a group, is optionally substituted with one or more halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b), -heteroaryl, -heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl, —NHheterocycle, or —S(O)₂NR_(c)R_(d); each Z¹⁴ is independently selected from —NO₂, ═NOR_(a), —CN, —(C₃-C₇)halocarbocycle, —O(C₃-C₇)halocarbocycle, —S(C₃-C₇)halocarbocycle, —S(O)(C₃-C₇)halocarbocycle, —SO₂(C₃-C₇)halocarbocycle, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)halocarbocycle, —NR_(a)SO₂Oaryl and —OS(O)₂R_(a), wherein any —(C₃-C₇)halocarbocycle of Z¹⁴, either alone or as part of a group, is optionally substituted with one or more halogen, —OH, —OR_(b), —CN, —NR_(a)C(O)₂R_(b), -heteroaryl, -heterocycle, —Oheteroaryl, —Oheterocycle, —NHheteroaryl, —NHheterocycle, or —S(O)₂NR_(c)R_(d); each R_(a) is independently H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryl(C₁-C₆)alkyl-, heteroaryl or heteroaryl(C₁-C₆)alkyl-, wherein any (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl or heteroaryl of R_(a), either alone or as part of a group, is optionally substituted by halogen, OH and cyano; each R_(b) is independently (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl, aryl(C₁-C₆)alkyl-, heteroaryl or heteroaryl(C₁-C₆)alkyl-, wherein any (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl or heteroaryl of R_(b) is optionally substituted by halogen, OH and cyano; R_(c) and R_(d) are each independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)carbocycle, aryl, aryl(C₁-C₆)alkyl-, heterocycle, heteroaryl and heteroaryl(C₁-C₆)alkyl-, wherein any (C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, (C₃-C₇)carbocycle, heterocycle, aryl and heteroaryl of R_(c) or R_(d), either alone or as part of a group, is optionally substituted by halogen, OH and cyano; or R_(c) and R_(d) together with the nitrogen to which they are attached form a heterocycle, wherein any heterocycle of R_(c) and R_(d) together with the nitrogen to which they are attached is optionally substituted by halogen, OH or cyano; each R_(e) is independently selected from —OR_(a), (C₁-C₆)alkyl and (C₃-C₇)carbocycle, wherein (C₁-C₆)alkyl and (C₃-C₇)carbocycle are substituted by one or more Z⁶ and optionally substituted with one or more Z¹, (C₂-C₆)haloalkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein any (C₂-C₆)haloalkyl, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl is optionally substituted with one or more Z¹, and aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are substituted by one or more Z⁵; each R_(f) is independently selected from —R_(g), —OR_(a), —(C₁-C₆)alkyl-Z⁶, —SO₂R_(g), —C(O)R_(g), C(O)OR_(g), and —C(O)NR_(e)R_(g); and each R_(g) is independently selected from H, —OR_(a), (C₁-C₆)alkyl, (C₃-C₇)carbocycle, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, wherein any (C₁-C₆)alkyl, (C₃-C₇)carbocycle, (C₁-C₆)haloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle or heteroaryl of R_(g) is optionally substituted with one or more Z¹ groups; or a salt thereof.
 2. The compound of claim 1 wherein R³ is (C₁-C₆)alkyl, (C₂-C₆)alkenyl or —O(C₁-C₆)alkyl wherein any (C₁-C₆)alkyl or (C₂-C₆)alkenyl of R³ is optionally substituted with one or more groups selected from —O(C₁-C₆)alkyl, halo, oxo and —CN; and wherein R^(3′) is H.
 3. The compound of claim 1 which is a compound of formula Ie:

or a salt thereof.
 4. The compound of claim 1 wherein R⁴ is selected from: a) aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl is optionally substituted with one or more groups each independently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo; b) (C₃-C₁₄)carbocycle, wherein (C₃-C₁₄)carbocycle is optionally substituted with one or more Z¹ groups, wherein two Z¹ groups together with the atom or atoms to which they are attached optionally form a (C₃-C₇)carbocycle or heterocycle; and c) aryl, heteroaryl and fused-heterocycle, wherein any aryl, heteroaryl and fused-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.
 5. The compound of claim 1 wherein R⁴ is selected from: a) aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl is optionally substituted with one or more groups each independently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and b) aryl, heteroaryl and fused-heterocycle, wherein any aryl, heteroaryl and fused-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.
 6. The compound of claim 1 wherein R⁴ is selected from: a) heterocycle, wherein heterocycle is optionally substituted with one or more groups each independently selected from halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, —OH, —O(C₁-C₆)alkyl, —SH, —S(C₁-C₆)alkyl, —NH₂, —NH(C₁-C₆)alkyl and —N((C₁-C₆)alkyl)₂, wherein (C₁-C₆)alkyl is optionally substituted with hydroxy, —O(C₁-C₆)alkyl, cyano or oxo; and b) fused-heterocycle, wherein fused-heterocycle is substituted with one or more Z⁷ groups and optionally substituted with one or more Z¹ groups.
 7. The compound of claim 1 wherein R⁴ is:


8. The compound of claim 1 wherein R⁴ is:


9. The compound of claim 1 wherein R¹ is selected from: a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl; b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, and wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; f) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and g) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹groups.
 10. The compound of claim 1 wherein R¹ is selected from: a) H, halo and (C₁-C₆)alkyl; b) (C₂-C₆)alkenyl, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; c) —C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; d) —(C₁-C₆)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹¹ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; f) aryl, heteroaryl and heterocycle, wherein any aryl heteroaryl and heterocycle is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and g) (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.
 11. The compound of claim 1 wherein R¹ is selected from:


12. The compound of claim 1 wherein R¹ is halo.
 13. The compound of claim 1 wherein R² is selected from: a) H, (C₁-C₆)alkyl and —O(C₁-C₆)alkyl; b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle, heteroaryl, halo, nitro and cyano; c) C(═O)—R¹¹, —C(═O)—O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z¹¹ groups; d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰, and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₅-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; and f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, and (C₂-C₆)alkynyl, wherein any (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.
 14. The compound of claim 1 wherein R² is selected from: a) (C₁-C₆)alkyl; b) (C₂-C₆)alkenyl and (C₅-C₆)haloalkyl; c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle or heteroaryl are each optionally substituted with one or more Z¹¹ groups; d) —(C₁-C₆)alkyl-N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; and f) (C₂-C₆)alkenyl, wherein (C₂-C₆)alkenyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹groups.
 15. The compound of claim 1 wherein R² is:


16. The compound of claim 1 wherein R² is methyl.
 17. The compound of claim 1 wherein R⁶ is selected from: a) H, halo, (C₁-C₆)alkyl, and (C₁-C₆)haloalkyl b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups; c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups; d) —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-S(O)—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₁-C₆)alkyl-SO₂—(C₁-C₆)alkyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-(C₁-C₆)haloalkyl, —(C₂-C₆)alkynyl-(C₁-C₆)haloalkyl, -halo(C₃-C₇)carbocycle, —NR_(a)SO₂NR_(c)R_(d), —NR_(a)SO₂O(C₃-C₇)carbocycle, —NR_(a)SO₂Oaryl, —(C₂-C₆)alkenyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkenyl-aryl, —(C₂-C₆)alkenyl-heteroaryl, —(C₂-C₆)alkenyl-heterocycle, —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl, —(C₂-C₆)alkynyl-heterocycle, —(C₂-C₈)alkynyl-OR_(a) and —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a), —(C₃-C₇)carbocycle-Z¹ and -halo(C₁-C₆)alkyl-Z³, wherein any (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heterocycle and heteroaryl, either alone or as part of a group, is optionally substituted with one or more Z¹ groups; e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; f) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and g) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein any (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.
 18. The compound of claim 1 wherein R⁶ is selected from: a) H, halo and (C₁-C₆)alkyl; b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl and aryl, wherein any aryl is optionally substituted with one or more Z¹⁰ groups; c) —(C₁-C₆)alkyl-R¹¹ and —(C₁-C₆)alkyl-O—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl of R⁶ is optionally substituted with one or more Z¹⁰ groups; d) —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl —(C₂-C₆)alkynyl-heterocycle, —(C₂-C₈)alkynyl-OR_(a) and —(C₂-C₆)alkyl-(C₃-C₇)carbocycle-OR_(a), wherein —(C₂-C₆)alkynyl-(C₃-C₇)carbocycle, —(C₂-C₆)alkynyl-aryl, —(C₂-C₆)alkynyl-heteroaryl and —(C₂-C₆)alkynyl-heterocycle, are optionally substituted with one or more Z¹ groups; e) (C₁-C₆)alky, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; f) aryl, wherein aryl is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; and g) (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.
 19. The compound of claim 1 wherein R⁶ is selected from:


20. The compound of claim 1 wherein R⁶ is H.
 21. The compound of claim 1 wherein R⁷ is selected from: a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl; b) (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₇)cycloalkyl, nitro, cyano, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle and heteroaryl is optionally substituted with one or more Z¹⁰ groups; c) —C(═O)—R¹¹, —C(═O)—O—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; d) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; e) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; f) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl, heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; g) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein any (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and h) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f), —(C₁-C₆)alkyl-NR_(e)R^(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f), —(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f), wherein each any (C₁-C₆)alkyl, either alone or as part of a group, is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.
 22. The compound of claim 1 wherein R⁷ is selected from: a) H, halo, (C₁-C₆)alkyl and (C₁-C₆)haloalkyl; b) (C₃-C₇)cycloalkyl, cyano, aryl and heteroaryl, wherein any aryl and heteroaryl is optionally substituted with one or more Z¹⁰ groups; c) —C(═O)—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein any aryl, heterocycle or heteroaryl is optionally substituted with one or more Z¹⁰ groups; d) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; e) aryl and heteroaryl, wherein aryl and heteroaryl are each substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₁-C₆)haloalkyl and (C₃-C₇)carbocycle, wherein (C₁-C₆)haloalkyl and (C₃-C₇)carbocycle are each substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —C(O)NR_(e)R_(f).
 23. The compound of claim 1 wherein R⁷ is selected from:


24. The compound of claim 1 wherein R⁷ is H.
 25. The compound of claim 1 wherein R⁸ is selected from: a) halo, nitro and cyano; b) R¹¹, —C(═O)—R¹¹, —C(═O)—R¹¹, —O—R¹¹, —S—R¹¹, —S(O)—R¹¹, —SO₂—R¹¹, —(C₁-C₆)alkyl-R¹¹, —(C₁-C₆)alkyl-C(═O)—R¹¹, —(C₁-C₆)alkyl-C(═O)—O—R¹¹, —(C₁-C₆)alkyl-O—R¹¹, —(C₁-C₆)alkyl-S—R¹¹, —(C₁-C₆)alkyl-S(O)—R¹¹ and —(C₁-C₆)alkyl-SO₂—R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹¹ groups; c) —N(R⁹)R¹⁰, —C(═O)—N(R⁹)R¹⁰, —O—C(═O)—N(R⁹)R¹⁰, —SO₂—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-N(R⁹)R¹⁰, —(C₁-C₆)alkyl-C(═O)—N(R⁹)R¹⁰, —(C₁-C₆)alkyl-O—C(═O)—N(R⁹)R¹⁰ and —(C₁-C₆)alkyl-SO₂—N(R⁹)R¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each Ro¹ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; d) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; e) aryl, heteroaryl, heterocycle, —Xaryl, —Xheteroaryl and —Xheterocycle, wherein any aryl heteroaryl and heterocycle, either alone or as part of a group, is substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl, wherein (C₁-C₆)haloalkyl, (C₃-C₇)carbocycle, (C₂-C₆)alkenyl and (C₂-C₆)alkynyl are each independently substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —NR_(e)R_(f), —C(O)NR_(e)R_(f), —OC(O)NR_(e)R_(f), —SO₂NR_(e)R_(f), —(C₁-C₆)alkyl-NR_(e)R_(f), —(C₁-C₆)alkylC(O)—NR_(e)R_(f), —(C₁-C₆)alkyl-O—C(O)—NR_(e)R_(f) and —(C₁-C₆)alkyl-SO₂NR_(e)R_(f), wherein any (C₁-C₆)alky, as part of a group, is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups.
 26. The compound of claim 1 wherein R⁸ is selected from: a) halo and cyano; b) R¹¹, —O—R¹¹ and —(C₁-C₆)alkyl-R¹¹, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl, wherein aryl, heterocycle and heteroaryl are each optionally substituted with one or more Z¹ groups; c) —C(═O)—N(R⁹)Ro¹⁰, wherein each R⁹ is independently selected from H, (C₁-C₆)alkyl and (C₃-C₇)cycloalkyl, and each R¹⁰ is independently selected from R¹¹, —(C₁-C₆)alkyl-R¹¹, —SO₂—R¹¹, —C(═O)—R¹, —C(═O)OR¹¹ and —C(═O)N(R⁹)R¹⁰, wherein each R¹¹ is independently selected from H, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₃-C₇)cycloalkyl, aryl, heterocycle and heteroaryl; d) (C₁-C₆)alkyl, wherein (C₁-C₆)alkyl is substituted with one or more Z² groups and optionally substituted with one or more Z¹ groups; e) aryl and heteroaryl, wherein aryl and heteroaryl are each independently substituted with one or more Z⁵ groups and optionally substituted with one or more Z¹ groups; f) (C₂-C₆)alkynyl, wherein (C₂-C₆)alkynyl is substituted with one or more Z⁶ groups and optionally substituted with one or more Z¹ groups; and g) —C(O)NR_(e)R_(f).
 27. The compound claim 1 wherein R⁸ is selected from:


28. The compound of claim 1 wherein R⁸ is H.
 29. The compound of claim 1 selected from:

and salts thereof.
 30. A pharmaceutical composition comprising a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
 31. A method of treating the proliferation of the HIV virus, treating AIDS or delaying the onset of AIDS or ARC symptoms in a mammal comprising administering a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, to the mammal. 32-34. (canceled) 